Treatment of circadian rhythm disorders

ABSTRACT

Embodiments of the invention relate to the use of a melatonin agonist in the treatment of free running circadian rhythms in patients, including light perception impaired patients, e.g., blind patients, and to methods of measuring circadian rhythm.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of co-pending U.S. provisionalpatent application Nos. 61/590,974, filed 26 Jan. 2012, 61/640,067,filed 30 Apr. 2012, 61/650,455, filed 22 May 2012, 61/650,458, filed 22May 2012, 61/714,149, filed 15 Oct. 2012, 61/738,985, filed 18 Dec.2012, 61/738,987, filed 18 Dec. 2012, and 61/755,896, filed 23 Jan.2013, each of which is hereby incorporated herein as though fully setforth.

FIELD OF THE INVENTION

Embodiments of the invention relate generally to the field of circadianrhythm disorders (CRDs) and, more particularly, to the entrainment ofcircadian rhythms in persons afflicted with Non-24 Hour Disorder(Non-24).

BACKGROUND OF THE INVENTION

The master body clock controls the timing of many aspects of physiology,behavior and metabolism that show daily rhythms, including thesleep-wake cycles, body temperature, alertness and performance,metabolic rhythms and certain hormones which exhibit circadianvariation. Outputs from the suprachiasmatic nucleus (SCN) control manyendocrine rhythms including those of melatonin secretion by the pinealgland as well as the control of cortisol secretion via effects on thehypothalamus, the pituitary and the adrenal glands. This master bodyclock, located in the SCN, spontaneously generates rhythms ofapproximately 24.5 hours. These non-24-hour rhythms are synchronizedeach day to the 24-hour day-night cycle by light, the primaryenvironmental time cue which is detected by specialized cells in theretina and transmitted to the SCN via the retino-hypothalamic tract.Inability to detect this light signal, as occurs in most totally blindindividuals, leads to the inability of the master body clock to be resetdaily and maintain entrainment to a 24-hour day.

Non-24-Hour Disorder

Non-24, also referred to as Non-24-Hour Sleep-Wake Disorder (N24HSWD) orNon-24-Hour Disorder, is an orphan indication affecting approximately65,000 to 95,000 people in the U.S. and 140,000 in Europe. Non-24 occurswhen individuals, primarily blind with no light perception, are unableto synchronize their endogenous circadian pacemaker to the 24-hourlight/dark cycle. Without light as a synchronizer, and because theperiod of the internal clock is typically a little longer than 24 hours,individuals with Non-24 experience their circadian drive to initiatesleep drifting later and later each day. Individuals with Non-24 haveabnormal night sleep patterns, accompanied by difficulty staying awakeduring the day. Non-24 leads to significant impairment, with chroniceffects impacting the social and occupational functioning of theseindividuals.

In addition to problems sleeping at the desired time, individuals withNon-24 experience excessive daytime sleepiness that often results indaytime napping.

The severity of nighttime sleep complaints and/or daytime sleepinesscomplaints varies depending on where in the cycle the individual's bodyclock is with respect to their social, work, or sleep schedule. The“free running” of the clock results in approximately a 1-4 monthrepeating cycle, the circadian cycle, where the circadian drive toinitiate sleep continually shifts a little each day (about 15 minutes onaverage) until the cycle repeats itself. Initially, when the circadiancycle becomes desynchronous with the 24 h day-night cycle, individualswith Non-24 have difficulty initiating sleep. As time progresses, theinternal circadian rhythms of these individuals becomes 180 degrees outof synchrony with the 24 h day-night cycle, which gradually makessleeping at night virtually impossible, and leads to extreme sleepinessduring daytime hours.

Eventually, the individual's sleep-wake cycle becomes aligned with thenight, and “free-running” individuals are able to sleep well during aconventional or socially acceptable time. However, the alignment betweenthe internal circadian rhythm and the 24-hour day-night cycle is onlytemporary.

In addition to cyclical nighttime sleep and daytime sleepiness problems,this condition can cause deleterious daily shifts in body temperatureand hormone secretion, may cause metabolic disruption and is sometimesassociated with depressive symptoms and mood disorders.

It is estimated that 50-75% of totally blind people in the United States(approximately 65,000 to 95,000) have Non-24. This condition can alsoaffect sighted people. However, cases are rarely reported in thispopulation, and the true rate of Non-24 in the general population is notknown.

The ultimate treatment goal for individuals with Non-24 is to entrain orsynchronize their circadian rhythms into an appropriate phaserelationship with the 24-hour day so that they will have increasedsleepiness during the night and increased wakefulness during thedaytime.

Tasimelteon

Tasimelteon is a circadian regulator which binds specifically to twohigh affinity melatonin receptors, Mel1a (MT1R) and Mel1b (MT2R). Thesereceptors are found in high density in the suprachiasmatic nucleus ofthe brain (SCN), which is responsible for synchronizing our sleep/wakecycle. Tasimelteon has been shown to improve sleep parameters in priorclinical studies, which simulated a desynchronization of the circadianclock. Tasimelteon has so far been studied in hundreds of individualsand has shown a good tolerability profile.

SUMMARY OF THE INVENTION

Embodiments of the invention relate to the discovery that tasimelteoncan be used to treat a free running circadian rhythm, in patients,including light perception impaired patients, e.g., blind patients, inwhom such free running circadian rhythm manifests itself as Non-24.

Embodiments of this invention further relate to the invention of amethod for determining a person's circadian rhythm (tau) and to theapplication of such methodology to the treatment of a free runningcircadian rhythm.

Embodiments of this invention further relate to the treatment ofsubjects who present with symptoms of Non-24, specifically, e.g., sleepdrifting later each day, abnormal night sleep patterns, and/ordifficulty staying awake during the day, leading in many cases tosignificant impairment, with chronic effects impacting the social andoccupational functioning of these individuals, as well as possiblenegative health effects of chronic misalignment.

Thus, in illustrative embodiments, the invention comprises a method ofdetermining the circadian period (τ) in a human subject, said methodcomprising:

-   a) collecting at least one biological sample from the patient during    each of a plurality of regular collection intervals (CIs) during at    least two Collection Sessions, each Collection Session being at    least 48 hours in duration;-   b) if multiple biological samples are collected during each CI, then    optionally physically pooling all samples collected within a given    CI and, in such case, assigning a Collection Time Point for each CI;-   c) measuring the amount (absolute or concentration) of melatonin or    of a melatonin surrogate in each of the samples or pooled samples;-   d) optionally converting the amount of melatonin or melatonin    surrogate at each Collection Time Point to a rate of production;-   e) analyzing the amount of melatonin or melatonin surrogate or the    rate of melatonin or melatonin surrogate production at each    Collection Time Point to model the patient's cycle, including the    acrophase, of melatonin or melatonin surrogate amount or production    on each day;-   f) fitting serial acrophase determinations to a weighted linear    regression model in order to determine τ, wherein τ=24+slope.

A further illustrative embodiment is a method of treating a humanpatient presenting symptoms of Non-24, said method comprisingdetermining the patient's τ by the method described above, and furtherdescribed below, if the patient's τ is longer than 24 hours, thentreating the patient by daily internally administering to the patient aneffective amount of a melatonin agonist.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an example of a patient report for a patient determined not tohave a free-running circadian rhythm based on aMT6s analyses.

FIG. 2 is an example of a patient report for a patient determined tohave a free-running circadian rhythm based on aMT6s analyses.

FIG. 3 is an example of a patient report for a patient determined not tohave a free-running circadian rhythm based on cortisol analyses.

FIG. 4 is an example of a patient report for a patient determined tohave a free-running circadian rhythm based on cortisol analyses.

FIG. 5 shows a metabolic pathway of tasimelteon and several of itsmetabolites.

FIGS. 6-11 show plots of the effect of co-administration of tasimelteonand fluvoxamine on the concentration of, respectively, tasimelteon, theM9 metabolite, the M11 metabolite, the M12 metabolite, the M13metabolite, and the M14 metabolite.

FIGS. 12-17 show plots of the effect of smoking on the concentration of,respectively, tasimelteon, the M9 metabolite, the M11 metabolite, theM12 metabolite, the M13 metabolite, and the M14 metabolite.

DETAILED DESCRIPTION OF THE INVENTION

Tasimelteon has the chemical name:trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1yl]methyl]propanamide,has the structure of Formula I:

and is disclosed in U.S. Pat. No. 5,856,529 and in US 20090105333, bothof which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about78° C. (DSC) and is very soluble or freely soluble in 95% ethanol,methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols(PEG-300 and PEG-400), and only slightly soluble in water. The native pHof a saturated solution of tasimelteon in water is 8.5 and its aqueoussolubility is practically unaffected by pH. Tasimelteon has 2-4 timesgreater affinity for MT2R relative to MT1R. It's affinity (K_(i)) forMT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful inthe practice of this invention because it is a melatonin agonist thathas been demonstrated, among other activities, to entrain patientssuffering from Non-24.

In related aspects, this invention relates to the use of a tasimelteonmetabolite as the melatonin agonist. Tasimelteon metabolites include,for example, a phenol-carboxylic acid analog (M9) and ahydroxypropyl-phenol analog (M11). Each is formed in humans followingoral administration of tasimelteon.

Specifically, aspects of the invention encompass use of tasimelteon orof compounds of Formulas II or III, including salts, solvates, andhydrates of tasimelteon or of compounds of Formula II or Formula III, inamorphous or crystalline form.

While depicted herein in the R-trans configuration, the inventionnevertheless comprises use of stereoisomers thereof, i.e., R-cis,S-trans, and S-cis. In addition, the invention comprises use of prodrugsof tasimelteon or of compounds of Formula II or of Formula III,including, for example, esters of such compounds. The discussion thatfollows will refer to tasimelteon but it is to be understood that thecompounds of Formula II and III are also useful in the practice ofaspects of the invention.

Metabolites of tasimelteon include, for example, those described in“Preclinical Pharmacokinetics and Metabolism of BMS-214778, a NovelMelatonin Receptor Agonist” by Vachharajani et al., J. PharmaceuticalSci., 92(4):760-772, which is hereby incorporated herein by reference.The active metabolites of tasimelteon can also be used in the method ofthis invention, as can pharmaceutically acceptable salts of tasimelteonor of its active metabolites. For example, in addition to metabolites ofFormula II and III, above, metabolites of tasimelteon also include themonohydroxylated analogs M13 of Formula IV, M12 of Formula V, and M14 ofFormula VI.

Thus, it is apparent that this invention contemplates entrainment ofpatients suffering free running circadian rhythm to a 24 hour circadianrhythm by administration of a circadian rhythm regulator (i.e.,circadian rhythm modifier) capable of phase advancing and/or entrainingcircadian rhythms, such as a melatonin agonist like tasimelteon or anactive metabolite of tasimelteon or a pharmaceutically acceptable saltthereof.

Other MT1R and MT2R agonists, i.e., melatonin agonists, can have similareffects on the master body clock. So, for example, this inventionfurther contemplates the use of melatonin agonists such as but notlimited to melatonin,N-[1-(2,3-dihydrobenzofuran-4-yl)pyrrolidin-3-yl]-N-ethylurea andstructurally related compounds as disclosed in U.S. Pat. No. 6,211,225,LY-156735 ((R)—N-(2-(6-chloro-5-methoxy-1H-indol-3yl)propyl)acetamide)(disclosed in U.S. Pat. No. 4,997,845), agomelatine(N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide) (disclosed in U.S. Pat. No.5,225,442), ramelteon((S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide),2-phenylmelatonin, 8-M-PDOT, 2-iodomelatonin, and 6-chloromelatonin.

Additional melatonin agonists include, without limitation, those listedin U.S. Patent Application Publication No. 20050164987, which isincorporated herein by reference, specifically: TAK-375 (see Kato, K. etal. Int. J. Neuropsychopharmacol. 2000, 3 (Suppl. 1): Abst P.03.130; seealso abstracts P.03.125 and P.03.127), CGP 52608(1-(3-allyl-4-oxothiazolidine-2-ylidene)-4-met-hylthiosemicarbazone)(See Missbach et al., J. Biol. Chem. 1996, 271, 13515-22), GR196429(N-[2-[2,3,7,8-tetrahydro-1H-fur-o(2,3-g)indol-1-yl]ethyl]acetamide)(see Beresford et al., J. Pharmacol. Exp. Ther. 1998, 285, 1239-1245),S20242 (N-[2-(7-methoxy napth-1-yl)ethyl]propionamide) (seeDepres-Brummer et al., Eur. J. Pharmacol. 1998, 347, 57-66), S-23478(see Neuropharmacology July 2000), S24268 (see Naunyn SchmiedebergsArch. June 2003), S25150 (see Naunyn Schmiedebergs Arch. June 2003),GW-290569, luzindole (2-benzyl-N-acetyltryptamine) (see U.S. Pat. No.5,093,352), GR135531 (5-methoxycarbonylamino-N-acetyltrypt-amine) (seeU.S. Patent Application Publication No. 20010047016), Melatonin ResearchCompound A, Melatonin Agonist A (see IMSWorld R&D Focus August 2002),Melatonin Analogue B (see Pharmaprojects August 1998), Melatonin AgonistC (see Chem. Pharm. Bull. (Tokyo) January 2002), Melatonin Agonist D(see J. Pineal Research November 2000), Melatonin Agonist E (see Chem.Pharm. Bull. (Tokyo) February 2002), Melatonin Agonist F (see Reprod.Nutr. Dev. May 1999), Melatonin Agonist G (see J. Med. Chem. October1993), Melatonin Agonist H (see Famaco March 2000), Melatonin Agonist I(see J. Med. Chem. March 2000), Melatonin Analog J (see Bioorg. Med.Chem. Lett. March 2003), Melatonin Analog K (see MedAd News September2001), Melatonin Analog L, AH-001 (2-acetamido-8-methoxytetralin) (seeU.S. Pat. No. 5,151,446), GG-012 (4-methoxy-2-(methylenepropylamide)indan) (see Drijfhout et al., Eur. J. Pharmacol. 1999, 382,157-66), Enol-3-IPA, ML-23 (N-2,4-dinitrophenyl-5-methoxy-tryptamine)(see U.S. Pat. No. 4,880,826), SL-18.1616, IP-100-9 (U.S. Pat. No.5,580,878), Sleep Inducing Peptide A, AH-017 (see U.S. Pat. No.5,151,446), AH-002 (8-methoxy-2-propionamido-tetralin) (see U.S. Pat.No. 5,151,446), and IP-101. Metabolites, prodrugs, stereoisomers,polymorphs, hydrates, solvates, and salts of the above compounds thatare directly or indirectly active can, of course, also be used in thepractice of this invention.

Melatonin agonists with a MT1R and MT2R binding profile similar to thatof tasimelteon, which has 2 to 4 time greater specificity for MT2R, arepreferred.

Tasimelteon can be synthesized by procedures known in the art. Thepreparation of a 4-vinyl-2,3-dihydrobenzofuran cyclopropyl intermediatecan be carried out as described in U.S. Pat. No. 7,754,902, which isincorporated herein by reference as though fully set forth.

Pro-drugs, e.g., esters, and pharmaceutically acceptable salts can beprepared by exercise of routine skill in the art.

In patients suffering a Non-24, the melatonin and cortisol circadianrhythms and the natural day/night cycle become desynchronized. Forexample, in patients suffering from a free-running circadian rhythm,melatonin and cortisol acrophases occur more than 24 hours, e.g., >24.1hours, prior to each previous day's melatonin and cortisol acrophase,respectively, resulting in desynchronization for days, weeks, or evenmonths, depending upon the length of a patient's circadian rhythm,before the melatonin, cortisol, and day/night cycles are againtemporarily synchronized.

Chronic misalignment of cortisol has been associated with metabolic,cardiac, cognitive, neurologic, neoplastic, and hormonal disorders. Suchdisorders include, e.g., obesity, depression, neurological impairments.

This invention shows that entrainment of the melatonin circadian rhythmis linked to entrainment of the cortisol circadian rhythm.

Thus, in one aspect, an illustrative embodiment of the inventionprovides a method of entraining a patient suffering from an abnormalmelatonin circadian rhythm, or an abnormal cortisol circadian rhythm, toa 24 hour circadian rhythm by internally administering to the patient aneffective amount of a melatonin agonist, in particular, tasimelteon oran active metabolite thereof.

In related aspects, this invention provides a method of preventing ortreating disorders associated with a desynchronous melatonin or cortisolcircadian rhythm, i.e., a circadian rhythm that is not synchronized withthe natural day/night cycle. Such method comprises internallyadministering to a patient having a desynchronous melatonin or cortisolcircadian rhythm an effective amount of a melatonin agonist, inparticular, tasimelteon or an active metabolite thereof, as described inthis specification.

The method of treating Non-24 (which includes phase advancing and/orentraining melatonin and/or cortisol circadian rhythm) in a patientsuffering therefrom by internally administering an effective amount oftasimelteon as described in this specification tends to be effectivemore often in patients having higher amounts of endogenous melatonin. Inother words, the likelihood of efficacy of treatment is related to theamount of melatonin naturally present in the patient's body.

The method of treating Non-24 (which includes phase advancing melatoninand/or cortisol circadian rhythm) in a patient suffering therefrom byinternally administering an effective amount of tasimelteon as describedin this specification tends to be effective more often in patients whosepre-treatment circadian rhythm (i.e., tau) is below a certain threshold.Such threshold can be, e.g., 25.0 hours, 24.9 hours, 24.8 hours, 24.7hours, 24.65 hours, or 24.6 hours, such that the likelihood of efficacyof treatment is greater in the case of patients whose tau is below thethreshold.

In accordance with this invention, a regulatory agency, a patient, ahealthcare provider, or an insurance provider, or any one or more ofsuch entities or persons, can choose a likelihood of efficacy that issufficient to support initiation of treatment with a melatonin agonist,in particular, tasimelteon. For example, it may be decided that if thelikelihood of efficacy is less than a selected threshold probability,then the patient should not be treated with the melatonin agonist.

Alternatively, such threshold probability can be used as a factor indetermining whether or not to apply a heightened standard of monitoringfor efficacy and/or adverse events. For example, it may be decided thatif the likelihood of efficacy is less than a selected thresholdprobability, then the patient will be examined for signs of efficacyand/or adverse events within about 6 to 9 weeks following initiation oftreatment. Such heightened monitoring can also comprise more frequentmonitoring and/or decreased tolerance for lack of apparent efficacy orfor occurrence of side effects. For example, if there is no or scantevidence of efficacy or if there are signs of adverse events, perhapseven minor or early signs, then the melatonin agonist treatment may bediscontinued or modified. Heightened monitoring may include requiring apatient to maintain a sleep diary which would may include, e.g., thepatient's recordation of sleep and wake times, frequency and duration ofnaps, sleep latency, duration of nighttime sleep, etc., such recordationbeing, e.g., in writing, digitally, or telephonically.

Efficacy for these purposes can be determined in a number of ways,including, e.g., by determining a patient's tau after initiation oftherapy and following at least one complete circadian cycle during whichthe patient has been treated, e.g., about 6 to about 9 weeks afterinitiation of therapy, or by examining the patient's physical oremotional health such as by subjecting the patient to a physicalexamination or to questioning about sleep patterns, side effects,daytime napping, general well-being, etc.

Short of terminating treatment, it may be decided, e.g., that thepatient should receive a different dose of the melatonin agonist or adifferent melatonin agonist, e.g., a different melatonin agonist havingthe pharmacological activity, i.e., MT1R and MT2R binding and relativebinding affinities, and t_(1/2), of tasimelteon.

The threshold probability discussed above can be correlated to athreshold concentration of melatonin in a biological sample taken from apatient. For example, melatonin levels can be directly measured insamples of blood, plasma, urine, saliva, etc., and the melatoninconcentration that corresponds to a selected threshold probability canbe ascertained. The concentration of melatonin that corresponds to theselected threshold probability can be referred to as the ThresholdConcentration.

Melatonin levels are generally determined (1) by measuring the amount ofthe primary urinary metabolite of melatonin, 6-sulphatoxymelatonin(aMT6s) collected every 2 to 8 hours over a 24 to 48 hour period, (2) bymeasuring melatonin levels in samples of saliva taken every 30 to 60minutes under dim light, or (3) by measuring melatonin levels in samplesof blood taken frequently, e.g., every 20 to 30 minutes. Such methodsare summarized, e.g., by Benloucif et al., J Clin Sleep Med, 4(1): 66-69(2008).

It is within the skill of the art, and therefore encompassed by thisinvention, to use any surrogate for melatonin concentrations or rates ofproduction for determining the length of the melatonin rhythm, i.e.,tau. For example, as specifically described herein, one may use amountsof aMT6s as a surrogate for amounts of melatonin and one may use thecortisol circadian rhythm or the aMT6s circadian rhythm as a melatonincircadian rhythm surrogate, i.e., the length of the circadian rhythm ofcortisol can be a surrogate for the length of the circadian rhythm ofaMT6s which can be a surrogate for the length of the melatonin circadianrhythm (i.e. tau). Alternatively or additionally, one may use cortisolas such melatonin surrogate.

In an illustrative embodiment, the amount of melatonin is indirectlymeasured such as by measuring the amounts of a melatonin surrogate,specifically, aMT6s in urine samples, and using such amounts to estimateacrophase and average and peak endogenous aMT6s amounts orconcentrations in blood.

In an illustrative embodiment, the melatonin surrogate is the rate ofaMT6s production as ascertained by measuring aMT6s in urine samples. Insuch case, the Threshold Concentration would actually be a rate ofexcretion expressed, e.g., in units of ng/hr. Such rate can bedetermined by measuring the concentration of aMT6s in an aliquot ofurine (ng/ml) and multiplying it by volume/time (ml/hr) of the totalurinary void from which the aliquot was derived, as more fully explainedbelow. This surrogate measure is used in this illustrative embodimentfor convenience only and it can readily be re-calculated as theconcentration of aMT6s in urine and expressed, e.g., in ng/ml units oras the absolute amount of aMT6s in urine and expressed, e.g., in ng ormg units. Such amounts, whether expressed as excretion rates,concentrations, or weights, can also be converted into similarlyexpressed amounts of melatonin.

For example, a patient having a peak aMT6s production rate, i.e.,excretion rate, of 1500 ng/hr in urine is a likely responder totasimelteon. Therefore, the Threshold Concentration can be set at 1500ng/hr aMT6s. Alternatively, the Threshold Concentration can also be setat 2000 ng/hr of urinary aMT6s (e.g., urine samples collected in 4 hourintervals and during a nighttime sleep period) or any convenient numbertherebetween, e.g., 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or1950 ng/hr. Alternatively, the Threshold Concentration can also be setat greater than 2000 ng/hr of urinary aMT6s, e.g., 2100, 2200, 2300,2400 or 2500 ng/hr.

A Threshold Concentration of 1500 ng/hr aMT6s is indicative of a greaterthan 50% probability that a given patient will respond to treatment,i.e., greater than 50% of a population of patients having a peak aMT6sconcentration in urine (or the melatonin concentration that isequivalent thereto in another biological sample) are expected to respondto treatment. Based on the study results reported above, it is expectedthat more than about 75%, or even more than about 80% or 90% of patientswill respond if they have peak aMT6s production rates in urine (orcorresponding melatonin concentrations in a biological sample) of 1500ng/hr or 2000 ng/hr.

If endogenous melatonin levels are used to predict likelihood of patientresponse and not for tau determination, then it is not necessary todetermine the rate of aMT6s excretion at time points, or spans oftimepoints, throughout a full day. Instead, e.g., the amount ofmelatonin, as inferred from aMT6s in urine, can be measured in urinecollected and pooled in a single batch over a 24 hour period or evenduring a shorter period. Indeed, in illustrative embodiments, melatoninlevels as indicated by aMT6s in urine or directly as melatonin in, e.g.,blood or saliva, can be measured at given time points once or multipletimes per day.

The ability to predict likelihood of response to drug is very importantto healthcare providers, e.g., physicians and patients, as well as tohealthcare reimbursement providers, e.g., providers of prescription druginsurance. Thus, in one embodiment, prior to initiation of treatment ofNon-24 with a melatonin agonist, e.g., tasimelteon, the patient istested to determine his or her endogenous melatonin levels, inparticular, his or her peak melatonin concentration. Such testing can becarried out using a biological sample, e.g., urine, blood, plasma, orsaliva using the methodologies described above or any other methodology.Because the method of this invention provides a probability of response,the method of determining peak melatonin concentration does not requireprecision. It is enough that it provide an estimate within, e.g., 20%,in which case, if the Threshold Concentration is set at 2000 ng/hrurinary aMT6s, a patient would be regarded as a likely responder if thepatient's peak aMT6s excretion in urine is determined to be 1600 ng/hror higher. Even less precision, e.g., within 25% or 30%, may beacceptable. As in the case of determining tau, other surrogates forendogenous melatonin levels can also be used.

A further aspect of this invention arises from the fact that certaintherapeutic agents are known to reduce endogenous levels of melatonin.Prominent among such agents are beta-adrenergic receptor antagonists,commonly referred to as “beta blockers”, which are commonly prescribedfor treatment of cardiac arrhythmias, myocardial infarction, congestiveheart failure, and hypertension. Beta blockers include, e.g.,alprenolol, altenolol, carvedilol, metoprolol, and propanolol, to name afew.

Thus, in one aspect, this invention comprises classifying Non-24patients who are receiving beta blocker therapy as poor responders tomelatonin agonist therapy. In this illustrative embodiment, suchpatients may not be subjected to a determination of peak melatoninconcentration but, instead, may be treated as if their melatoninconcentrations are below a Threshold Concentration. Other factors thatmay have an adverse effect on efficacy are NSAIDs and light.

In a related illustrative embodiment, a Non-24 patient may be directedto submit to a determination of melatonin concentration because he orshe is being treated with beta blocker therapy to ascertain whether ornot the beta blocker therapy is in fact causing the patient's peakmelatonin level to drop below a Threshold Concentration.

In related aspects of this invention, plasma melatonin levels or betablocker therapy, or both, are used as efficacy predictors in combinationwith other markers of efficacy or adverse events. So, for example, anillustrative embodiment of this invention comprises treating a patientsuffering from Non-24 with tasimelteon if the patient has peak melatoninlevels corresponding to 1500 ng/hr (or 2000 ng/hr) of aMT6s in urinecollected during 4 hour periods or a nighttime sleep period and if thepatient is positive for one or more additional efficacy markers.Incorporation of such additional efficacy marker or markers can enhancethe ability of a healthcare provider to assess the likelihood that apatient suffering a non-24 hour circadian rhythm will benefit fromtreatment with a melatonin agonist such as tasimelteon.

In related embodiments, a computer-based system receives informationabout a prescription for tasimelteon and operates to associate thatinformation with information about the patient's endogenous melatoninlevels to output a report indicating a probability of efficacy or tooutput a report stating that a higher or lwere dose of tasimelteon, e.g,<20 mg/d or >20 mg/d, is indicated.

Patients can be diagnosed as suffering from Non-24 by estimating eachpatient's circadian period (tau). Patients whose tau exceeds 24 hoursare diagnosed as having Non-24. Thus, in general, Non-24 patients whocan benefit from treatment with tasimelteon have a tau, such as may bedetermined by analyzing the aMT6s or cortisol circadian rhythm, that islonger than 24 hours, e.g., greater than about 0.1 hours longer than 24hours and in some cases, at least about 0.2, 0.3, 0.4 and as large asabout 1.4 hours longer than 24 hours. As discussed herein, the cortisolcircadian rhythm can be used in place of or in addition to the aMT6srhythm, although cortisol circadian rhythm calculations may be slightlyless precise in the sense that such data compiled from analyses of apopulation of patients may exhibit a larger standard deviation.

To monitor circulating melatonin cycles in a subject, it is convenientto assay for levels of the major metabolite of melatonin, which is6-sulfatoxymelatonin (aMT6s) in urine, as its pattern of productioncorrelates closely with circulating melatonin levels. However, thisinvention contemplates measurement of aMT6s levels in other bodilysamples such as blood, e.g., plasma, or saliva and it also contemplatesdirect measurement of melatonin or of other surrogates for melatoninlevels. It is within the skill of the art to correlate levels oftasimelteon or tasimelteon metabolites in other bodily samples (i.e.,other than aMT6s in urine) with circulating melatonin levels. Forexample, the amounts of cortisol in blood or urine can be used in amanner similar to the use of aMT6s to determine tau.

A useful protocol for estimating tau in candidates for clinical testingfor treatment of Non-24, which method can be applied to diagnosis ofNon-24 in a given patient, is as follows:

-   -   Each subject will undergo four 48-hour urine collection sessions        at nominal days 7, 14, 21, and 28. During each session, the        start of the session and the time of each void will be recorded.        Urine collected over periods of 4 hours (with the first 4 hour        collection period of the day beginning at scheduled wake time),        or about 8 hours during sleep, will be pooled (the “collection        interval”); thus, subjects will have a total of 10 urine        collection intervals during each 48-hour period. A study nurse        will determine the volume of urine collected during each        interval (urine will be transferred to a graduated cylinder) and        an aliquot will be assayed for aMT6s.    -   For each collection interval, the start and end time of the        interval will be used to determine the midpoint and duration of        the interval. The start time of a given interval is defined as        the last void time from the prior 4 hour (or 8 hour) collection        interval; the end time of a given interval is defined as the        last void time within the collection interval.    -   The mass of the primary melatonin metabolite (aMT6s) excreted        during the interval will be determined as the product of aMT6s        concentration and volume of urine. Rate of aMT6s excretion will        be determined as the mass of aMT6s excreted divided by the        duration of the interval. This rate will be associated with the        midpoint of the interval, referenced to the midnight preceding        the start of the first interval in that session.    -   For example, if a collection interval on Day 27 runs from 9 AM        to 1 PM (and the patient had a void at exactly 9 AM and a void        at exactly 1 PM), midpoint of that interval would be assigned        the value 11.0. A comparable interval on the next day of that        session would be assigned a value 35.0.    -   To accommodate changes in the clock time due to Daylight Savings        Time changes, no urine collections will occur on a day that the        clock changes. For screening there will be occasions when the 4        different weeks that urine collections are conducted will span a        change in the clock time. Therefore, all urine collection times        will be automatically translated into local standard time for        calculations and then translated back to DST for reporting        purposes, if appropriate.    -   In certain situations, urine collections or their recording will        be incomplete. The following procedures will be invoked to        address this:    -   1. If a subject fails to timestamp a void, no action will be        taken if there are multiple voids with timestamps within one        interval.    -   2. If there is only one void in a collection interval, and the        patient cannot recall the time of the void then the entire 48        hour collection period will be excluded from the analysis and        the subject will be requested to collect an additional 48 hours        of urine after Day 28. It would not be possible to accurately        determine to which collection interval the unmarked urine        belongs. Consequently, the appropriate assignment of start and        stop times to all of the collection intervals would be        questionable.    -   3. If a void is discarded by the patient but the time of the        void is known, duration associated with that void (time of the        void minus the time of the previous void) will be subtracted        from the total duration associated with that interval. This        modified duration will be used to calculate rate of aMT6s        excretion. If a discarded sample is either the first or last of        the samples in an interval, the midpoint of that interval will        be calculated without considering that sample.    -   4. If fewer than 4 samples are available for one 48-hour        collection session, fitting of the cosine will be compromised        (inadequate degrees of freedom). Consequently, acrophase will        not be determined if fewer than four samples are available.    -   For each session, acrophase will be determined by fitting a        cosine to the data from that session using unweighted non-linear        regression. Fitting will be performed using a non-linear least        squares fitting algorithm. The fitting process will estimate        phase shift, mesor, and amplitude and their respective standard        errors; period of the cosine will be fixed to 24 hours.*        *Although these subjects are presumed to have a tau>24 hours,        attempts to estimate tau led to consistently poor results with        multiple test datasets. Steven Lockley, Ph.D., an expert in the        field uses this approach.    -   Acrophase will be determined as the phase shift modulus 24        hours.    -   If acrophase values are available for three or more sessions,        tau will be calculated using the following procedure:    -   1. Acrophase will be recalculated relative to day 0 (24•start        day for each session+acrophase).    -   2. These values will be regressed against start day for each        session using weighted linear regression. Weighting will be by        the inverse square of the standard error associated with the        estimate for acrophase for each session.

Thus, related to this invention is a method for determining a patient'scircadian rhythm (tau) and for treating a patient with a melatoninagonist, in particular, tasimelteon, based on that patient's tau. Inillustrative embodiments, the method of determining tau and treating apatient based on the patient's tau, in particular, based upon time ofaMT6s acrophase, comprises steps (a) through (f), as follows:

a) collecting at least one biological sample from the patient duringeach of a plurality of regular collection intervals (CIs) during atleast two Collection Sessions, each Collection Session being at least 48hours in duration;

b) if multiple biological samples (i.e., samples of the same type) arecollected during each CI, then optionally physically pooling all samplescollected within a given CI and, in such case, assigning a CollectionTime Point for each CI;

c) measuring the amount (absolute or concentration) of melatonin or of amelatonin surrogate in each of the samples or pooled samples;

d) optionally converting the amount of melatonin or melatonin surrogateat each Collection Time Point to a rate of production;

e) subjecting the amount of melatonin or melatonin surrogate or the rateof melatonin or melatonin surrogate production at each Collection TimePoint to cosinor analysis to model the patient's cycle, including theacrophase, of melatonin or melatonin surrogate amount or production oneach day;

f) fitting serial acrophase determinations to a weighted linearregression model in order to determine tau (τ), wherein τ=24+slope.

While cosinor analysis is mentioned above, it will be appreciated thatother methods can be used, e.g., a 2-harmonic fit analysis, inparticular, for cortisol rhythm analysis.

Following such determination of τ, a patient can be treated with amelatonin agonist, e.g., tasimelteon, such as described in step (g), asfollows:

g) if the patient's τ is longer than 24 hours, then:

-   -   (i) projecting the patient's acrophase for each of at least 30        days following Day 2 of the final Collection Session by adding τ        to the acrophase of said final Day 2 and to each day thereafter        and    -   (ii) treating the patient by daily internally administering to        the patient an effective amount of the melatonin agonist prior        to sleep time, beginning on the night of the Optimal Treatment        Initiation Day, or on a night within the Optimal Treatment        Initiation Window, during a succeeding circadian cycle.

The Optimal Treatment Initiation Day is the day on which the patient'ssleep time is expected to be closest to what it would be if the patienthad a normal, i.e., 24 hour, i.e., <24.1 hr, tau. Such day is generallythe day of the night on which the patient's melatonin (or melatoninsurrogate) acrophase is projected to be the optimal acrophase, i.e., thetime at which acrophase would occur if the patient had a normalcircadian rhythm. It is not necessary to initiate treatment precisely onthe Optimal Treatment Initiation Day but it is recommended thattreatment be initiated on such day or within a range of days on eitherside of such day, said range being referred to herein as the OptimalTreatment Initiation Window. Said window generally comprises the OptimalTreatment Initiation Day and (a) the immediately following days on whichthe melatonin (or surrogate) acrophase is projected to occur no laterthan about 3.5 hours (e.g., 3 hours, 3.5 hours or 4 hours) later thanthe optimal melatonin (or surrogate) acrophase and (b) the immediatelypreceding days on which melatonin (or surrogate) acrophase is projectedto occur no earlier than 5 hours earlier than the optimal melatonin (orsurrogate) acrophase.

For the sake of convenience, the Optimal Treatment Initiation Window canbe conveniently defined as a set number of days before and after theprojected Optimal Treatment Initiation Day, e.g., 2 days before and 2days after, for a defined Optimal Treatment Initiation Window comprisinga total of 5 days. Such window is illustrated in FIG. 2 wherein thefirst Optimal Treatment Initiation Day is Dec. 4, 2010 and the OptimalTreatment Initiation Window is defined for convenience as Dec. 2, 2010to Dec. 6, 2010.

It will be appreciated, however, that the window can be customized assummarized above based on a given patient's tau, i.e., depending uponhow fast a patient's circadian rhythm is running, such that a patientwith a relatively fast-moving circadian rhythm will have a narroweroptimal window than a patient with a relatively slow-moving circadianrhythm.

Normal monitoring can comprise step (h), as follows:

h) following a treatment period of at least one complete circadian cycle(based on the patient's pre-treatment tau) assessing entrainment asfollows:

-   -   (i) If τ is <24.1 hours with a 95% Confidence Interval that        crosses 24.0 hours, then the patient is considered to be        entrained to a 24 hour day;    -   (ii) If the last two acrophase estimates are within the target        range, i.e., −2 to +6 hours from optimal acrophase, and the        Standard Deviations of these two acrophases overlap, then,        taking an additional biological sample collection and        re-calculating τ based on the last three acrophase estimates        (the original two+the additional) and if tau is <24.1 hours with        a 95% Confidence Interval that crosses 24.0 hours, the patient        is considered to be entrained to a 24 hour day;    -   (iii) If τ>=24.1 hours or the 95% Confidence Interval does not        cross 24.0 hours, then the patient is retested.

The duration of a complete circadian cycle will vary depending upon therate at which a given patient is free running. For example, withreference to FIG. 2, a patient having a tau of 24.6 hours will completea circadian cycle in approximately 39 days (e.g., Dec. 4, 2010 to Jan.13, 2011). A patient with a slower rhythm, e.g., tau=24.5, will have alonger cycle and, conversely, a patient with a faster rhythm, e.g.,tau=24.7, will have a shorter cycle.

The tau determination and treatment method generally described above cancomprise any one or any combination of any two or more of the followinglimitations:

1. melatonin amounts are indirectly measured by measuring the amounts ofa melatonin surrogate, said surrogate being aMT6s.

2. the biological sample is urine, all urine collected during a given CIis physically pooled, and the mid-point of the CI is assigned as theCollection Time Point for that CI.

3. each CI during wake time is 4 hours and sleep time is a single CI,provided that samples are not collected during the first four hourperiod of each Collection Session or, if collected, are not used in thedetermination of tau.

4. the Collection Time Point for each CI is defined as the mid-pointbetween the time of the last urine void in the CI immediately precedinga given CI and the last urine void in the given CI.

5. there are 4 Collection Sessions.

6. there are 48 hours in each Collection Session.

7. Collection Sessions are conducted once per week.

8. the Optimal Treatment Initiation Day is the day of the night on whichthe melatonin or melatonin surrogate acrophase is projected to be theoptimal acrophase.

9. the optimal acrophase is the time at which aMT6s acrophase isprojected to be closest to and no later than about 3.5 hours prior tothe patient's target wake time.

10. the Optimal Treatment Initiation Window comprises the OptimalTreatment Initiation Day and (a) the immediately following days on whichthe melatonin acrophase is projected to occur no later than 3 hourslater than the optimal acrophase and (b) the immediately preceding dayson which melatonin acrophase is projected to occur no earlier than 5hours earlier than the optimal acrophase. In such embodiments, cortisolcan be used in place of aMT6s with adjustment to account for thedifference between the cortisol circadian rhythm and the aMT6s circadianrhythm.

11. treatment comprises internal administration of an effective amountof tasimelteon once per day, the time of administration being about 5hours prior to the time of the optimal aMT6s acrophase, and whereintreatment is continued daily for at least one complete circadian cycle.In such embodiments, cortisol can be used in place of aMT6s withadjustment to account for the difference between the cortisol circadianrhythm and the aMT6s circadian rhythm.

12. the amounts of melatonin or melatonin surrogate are measured inabsolute units or in concentration units.

13. the amount of melatonin or melatonin surrogate in the biologicalsample is determined as the product of the aMT6s concentration(mass/volume) and the volume of the biological sample.

14. the rate of melatonin or melatonin surrogate production isdetermined as the mass of melatonin or melatonin surrogate produced andcollected during each CI divided by the duration of the CI.

15. the rate of production is expressed as g/hr.

16. no samples are collected on a day that the clock changes to or fromDaylight Savings Time (DST) and, if the Collection Sessions span achange in the clock time, all Collection Time Points are translated intolocal standard time for calculations and then translated back to DST orstandard time, as appropriate, for reporting purposes.

17. samples are collected in a sample collection container by thepatient and provided to a laboratory for analysis, e.g., a diagnosticlaboratory.

18. the patient records the date and time of each sample collection on alabel that has been previously fixed to the collection container or thatis applied to the collection container by the patient.

19. the date and time of each collection are printed onto the label bytimestamp clock.

20. the biological sample is urine and melatonin amounts are indirectlymeasured by measuring the amounts of aMT6s and wherein if urinecollections or their recordings are incomplete, then:

(i) if a patient fails to timestamp a void, no action is taken if thereare multiple voids with timestamps within one CI;

(ii) if there is only one void in a CI and the patient cannot recall thetime of the void, then the entire 48 hour Collection Session is excludedfrom the analysis and an additional Collection Session is conducted;

(iii) if a void is discarded by the patient but the time of the void isknown, the duration associated with that void (time of the void minusthe time of the previous void) is subtracted from the total durationassociated with that CI and the modified duration is used to calculatethe rate of aMT6s production but if a discarded sample is either thefirst or last of the samples in a given CI, then the midpoint of that CIwill be calculated without considering that sample; provided that, iffewer than 4 samples are available for any one Collection Session,acrophase will not be determined for that Collection Session.

21. in step (h), if τ>=24.1 hours or the 95% Confidence Interval doesnot cross 24.0 hours, then treatment is continued and the patient isretested after a second complete circadian cycle.

22. in step (g), if the patient's τ is longer than 24 hours, e.g.,τ>=24.1 hours, the patient's acrophase is projected for each of the 90days following Day 2 of the final Collection Session.

23. aMT6s or cortisol is extracted from pooled urine samples by solidphase extraction, the extracts are evaporated to dryness, the residue isthen reconstituted with solvent, and the solution is analyzed byHPLC-MS, an antibody binding assay, or other analytical technique.

Thus, a particular illustrative embodiment of a method of determiningtau and thereafter treating a patient thereby determined to have afree-running circadian rhythm is as follows:

a) collecting and, if more than one, physically pooling urine samplesfrom the patient during each of 9 Collection Intervals (CIs) during fourweekly 48 hour collection sessions, said 9 CIs being CI2, CI3, CI4, CI5,CI6, CI7, CI8, CI9, and CI10, as follows:

CI1: 4 hour period beginning approximately on initiation of wake time ofDay 1 of the first Collection Session;

CI2: 4 hour period beginning at the end of CI1;

CI3: 4 hour period beginning at the end of CI2;

CI4: 4 hour period beginning at the end of CI3;

CI5: Overnight, i.e., sleep time (approx 8 hours),

CI6: 4 hour period beginning approximately on initiation of wake time ofDay 2 of the collection session;

CI7: 4 hour period beginning at the end of CI6;

CI8: 4 hour period beginning at the end of CI7;

CI9: 4 hour period beginning at the end of CI8;

CI10: Overnight, i.e., sleep time (approx 8 hours),

b) (i) optionally collecting and discarding samples during CI1 and (ii)assigning the mid-point between the last void of each CI immediatelypreceding a given subsequent CI and the last void of the givensubsequent CI as the Collection Time Point for each of CI2, CI3, CI4,CI5, CI6, CI7, CI8, CI9, and CI10;

c) measuring the amount of aMT6s or cortisol in each of the ten samples;

d) converting the measured amount of aMT6s or cortisol at eachCollection Time Point to a rate of production;

e) subjecting the rate of aMT6s or cortisol production rate at eachCollection Time Point to cosinor analysis to model the cycles, includingthe acrophase, of aMT6s or cortisol production on each day;

f) fitting serial acrophase determinations to a weighted linearregression model in order to determine circadian period (τ), whereinτ=24+slope (p</=0.05);

g) if the patient's τ is longer than 24 hours, then:

-   -   (i) projecting the patient's acrophase for each of the 90 days        following Day 2 of the final Collection Session by adding τ to        the acrophase of said final Day 2 and to each day thereafter and    -   (ii) treating the patient by daily internally administering to        the patient an effective amount of tasimelteon prior to sleep        time, beginning on the night of the Optimal Treatment Initiation        Day, or on a different night within the Optimal Treatment        Initiation Window, during the next succeeding circadian cycle

h) following a treatment period of one complete circadian cycle,assessing entrainment as follows:

-   -   (i) if τ is <24.1 hours with a 95% Confidence Interval that        crosses 24.0 hours, then the patient is considered to be        entrained to a 24 hour day;    -   (ii) if the last two acrophase estimates are within the target        range, i.e., −2 to +6 hours from optimal acrophase, and the        Standard Deviations of these two acrophases overlap, then,        taking an additional 48-hour urine collection and recalculating        τ based on the last three acrophase estimates (the original        two+the additional) and if tau is <24.1 hours with a 95%        Confidence Interval that crosses 24.0 hours, the patient is        considered to be entrained to a 24 hour day;    -   (iii) if τ>=24.1 hours or the 95% Confidence Interval does not        cross 24.0 hours, then the patient is retested with an        additional four 48-hour urine collection scheduled beginning 1        circadian cycle from the first collection.

It will be apparent that in the urine collection and analysis methodsthat may be used in the practice of aspects of this invention, it is notessential to use the entire volume of urine collected during eachCollection Interval.

The method of treatment of Non-24 by internally administering aneffective amount of a melatonin agonist, in particular, tasimelteon, isnot dependent upon the method for diagnosing or monitoring patients.Instead, said method of treatment is useful in treating Non-24 patientsregardless of how diagnosed. Similarly, other markers may be used topredict urinary aMT6s or cortisol acrophase.

Non-entrained persons, i.e., persons with a non-24 hour circadianrhythm, may exhibit symptoms of Non-24 with a clearly non-24 hour sleepperiod such that initiation of sleep and waking times, unlessartificially interrupted, begin later each succeeding day. Otherpatients may exhibit less severe shifts in sleep period and asignificant number may exhibit no shift in sleep period. Such patients,particularly those who do not exhibit shift in sleep period, can bemisdiagnosed as having a normal tau if the diagnosis is based solely onsleep and wake times. Some patients that exhibit mild or no shift insleep period may have cyclic patterns of one or more of sleep latency,nighttime sleep duration and daytime naps. Regardless of the sleepproblem, patients with non-24 hour circadian rhythms may be at risk forother circadian-related disorders, for example, metabolic disorders.

Entrainment of patients diagnosed as suffering from a non-24 hourcircadian rhythm, including Non-24, can be effected by initiatinginternal administration of a melatonin agonist like tasimelteon or anactive metabolite of tasimelteon or a pharmaceutically acceptable saltthereof, at any time or treatment can be initiated on or about a day onwhich the patient's melatonin acrophase (based, e.g., on urinary aMT6sacrophase) is predicted to occur about 3 to 4 hours, or about 3.5 hours,e.g., 3.25 hrs to 3.75 hrs, prior to a target wake time selected for orby a given patient. The “ideal” day for initiation of treatment can bemore explicitly defined as the day when the subject's predictedacrophase is both 1) closest to 3.5 hours prior to target wake time and2) earlier than that time. The latter qualifier makes it more likelythan not that treatment initiation will occur in a phase-advance part ofthe phase response curve.

For example, treatment of a patient who has a target bedtime of 10:00p.m. and a target wake time of 7:00 a.m., treatment initiation can be ona day when urinary aMT6s acrophase is predicted to occur at 3:30 am.However, treatment with tasimelteon can conveniently be initiated on aday on which melatonin acrophase, e.g., using calculated urinary aMT6sacrophase, is predicted to be between about 5.5 hours before target waketime and 2.5 hours after target wake time. Without intending to be boundto a particular theory, this flexibility is apparently owing to theunusually marked effects of such active ingredient on circadian rhythmupon initiation of treatment (e.g., phase advance by as much as about 5hours on initial treatment).

If a marker for circulating melatonin levels other than urinary aMT6s isemployed, e.g., aMT6s in plasma, then the above times would be adjustedaccordingly but would nevertheless be indirectly indicative of urinaryaMT6s levels.

In patients suffering Non-24, a calendar day may not be associated withan acrophase. For example, if a subject's tau is 24.5 hours andacrophase occurs at 23:45 (11:45 pm) on 28 August, the next acrophase ispredicted to occur at 00:15 (12:15 am) on 30 August.

In addition to entraining a Non-24 patient's tau to 24 hours, e.g.,<24.1 hours, a melatonin agonist, in particular, tasimelteon, can alsoincrease total sleep time per day and reduce total nap time per day.

Entrainment of a patient can be determined by various methods, includingby determining the patient's tau by the above-described or differentmethodologies. In addition, or alternatively, a patient's or ahealthcare worker's perception of improvement can be assessed such as byuse of a questionnaire. Such perception could utilize, e.g., theClinical Global Impression of Change (CGI-C),

The CGI-C is a healthcare worker-rated assessment of change in globalclinical status, defined as a sense of well-being and ability tofunction in daily activities. See, e.g., Lehmann E., Pharmacopsychiatry1984, 17:71-75. It is a 7 point rating scale whereby clinicians,physicians, or other healthcare workers rate a patient's improvement insymptoms relative to the start of the study. It is rated as: 1, verymuch improved; 2, much improved; 3, minimally improved; 4, no change; 5,minimally worse; 6, much worse; or 7, very much worse.

The questionnaire can be administered prior to or early followinginitiation of treatment, e.g., prior to Day 1 or, e.g., on Day 56(counted from first day of treatment) and it can be re-administeredlater following initiation of treatment, e.g., Day 112 and/or Day 183.

Due to the cyclicality of Non-24, a patient's overall improvement shouldnot be assessed at one time-point/visit. Consequently, the average scoreof CGI-C in the last two scheduled assessments (e.g., Day 112 and Day183) can be used to evaluate the patient's overall improvement.

In addition to or as an alternative to measuring a patient's taufollowing a period of treatment and/or utilizing patient or healthcareworker assessment such as by use of the CGI-C, various sleep parameterscan also be used to assess efficacy of treatment, i.e., entrainment.

For example, sleep parameters that can be assessed include one or moreof Lower Quartile of Nights of nTST (LQ-nTST), Upper Quartile of Days ofdTSD (UQ-dTSD), and Midpoint of Sleep Timing (MoST).

Lower Quartile of Nights of nTST (LQ-nTST)

Patients suffering from Non-24 may have trouble sleeping as a result oftheir sleep cycle being out of synchrony with the 24 hour clock. Thisleads to intervals of poor sleep followed by intervals of good sleep.Therefore, the severity of symptoms associated with Non-24 is bestillustrated when isolating the worst nights of sleep and the days withthe most naps. Evaluating the 25% worst nights of sleep of an individualserves as a good measure of how an individual is suffering from thiscircadian disease in relationship to nighttime total sleep time (nTST).

The method for calculating the LQ-nTST is described as follows. For agiven individual, all non-missing values (must include >70% of onecircadian cycle for both baseline and randomized data) of nighttimetotal sleep time are ordered from smallest to largest. The first 25%(ceiling(number of non-missing records)/4) of the records are flagged asbelonging to the lower quartile of nighttime total sleep time. Theaverage of these values is calculated and this result is denotedLQ-nTST.

For example, assume that a subject has 21 nTST baseline records: 6.75,6.75, 1, 1, 6.75, 1.083, 7.167, 0.833, 7.083, 7.983, 7, 7, 7.833, 7,7.667, 7.183, 7, 7.067, 7, 7.183, and 7.

These are rank ordered and the first 25% of records are selected[(21/4)=6]: 0.833, 1, 1, 1.083, 6.75, and 6.75.

Those values are averaged to obtain the subject's LQ-nTST:(0.833+1+1+1.083+6.75+6.75)/6=2.91.

Upper Quartile of Days of dTSD (UQ-dTSD)

Patients suffering from Non-24 have a propensity to sleep during the dayas a result of their sleep cycle being out of synchrony with a 24 hourclock including daytime napping. In contrast, they may have very littleor no napping when their circadian rhythms are aligned with the 24-hourday. In order to measure the effect of this dynamic circadian disorderon daytime napping a robust assessment for measuring the worst of thedaytime napping, the 25% worst days will be used for this calculation ina similar fashion as for LQ-nTST.

The method for calculating the UQ-dTSD is described as follows. For agiven individual, all non-missing values of daytime total nap durationsare summed for a given day and then these daily summations are rankordered from largest to smallest (Note: days for which an individualreported no nap are recorded as zero). The first 25% (ceiling(number ofnon-missing records)/4) of the records are flagged as belonging to theupper quartile of daytime total sleep duration (dTSD). The average ofthese values is calculated and this result is denoted UQ-dTSD.

For example, assume that a subject has 26 dTSD baseline records: 1.083,1.083, 1.083, 1.083, 1.083, 1.083, 1.083, 1.083, 1.083, 1.083, 1.083,1.083, 1.083, 1.083, 1.083, 1.083, 1.083, 0, 1.083, 1.667, 1.083, 1.083,1.083, 1.083, 1.083, and 1.083.

These are rank ordered (largest to smallest) and the first 25% ofrecords, i.e., ceiling(26/4)=7 records identified: 1.667, 1.083, 1.083,1.083, 1.083, 1.083, and 1.083.

These values are averaged to obtain the subject's UQ-dTSD:(1.667+1.083+1.083+1.083+1.083+1.083+1.083)/7=1.17.

Midpoint of Sleep Timing (MoST)

Circadian rhythm disorders, including Non-24, are characterized by atiming misalignment of the circadian rhythms to the 24-hour light-darkcycle and hence the activities that an individual is performing (e.g.,attempting to sleep at night when the circadian rhythms are signalingthe brain to be awake). Midpoint of sleep timing is derived from acombination of the sleep reported in both the pre- and post-sleepquestionnaires. The midpoint of sleep timing over a 24 hour period(adjusted to be relative from −12 hours before bedtime until +12 hoursafter bedtime) can be calculated for each day. The first step incalculating the midpoint is to calculate the midpoint and weight, e.g.,duration, for each sleep episode. The total 24-hour sleep time is thesummation of all sleep episodes in this 24 hour period. Each of theindividual sleep episodes is then assigned a weight relative to thefraction of 24 hour sleep that it contains.

A useful MoST algorithm can be summarized as follows:

1. calculate the midpoint and weight, i.e., duration, for each sleepepisode in a given 24 hour period;

2. assign a weight to each sleep episode;

3. determine the average of the weighted sleep episodes; and

4. correct the average of the weighted sleep episodes for targetbedtime.

More specifically, such useful algorithm may be further defined asfollows:

the midpoint for each sleep episode in a 24 hour period is calculated asfollows:

Sleep Start Time+[(Sleep End Time−Sleep Start Time)/2]−24;

the weight of each sleep episode is equal to the duration of sleep (asperceived or objectively measured);the weighted value of each sleep episode is calculated as follows:

midpoint*(weight/TST)

where TST is the sum of all sleep durations in the 24 hour period; theaverage of the weighted sleep episodes is the sum of the weighted valuesof all sleep episodes divided by the number of sleep episodes; and thecorrection for target bedtime is calculated as follows:

24−target bedtime+average of weighted sleep episodes.

For example, assuming an individual with a target bedtime of 10:30 PMwent to sleep at 10:30 PM and woke up at 6:30 AM (with a self-reportedtotal sleep time of 5 hours). Assuming, also, that he/she took a nap at8:05 PM that lasted 2 hours and 5 minutes. The mid-point of sleep timing(MoST) for that day would be 1.959559 (relative to the target bedtime),calculated as follows.

Nighttime Sleep Midpoint:

Sleep Start Time=Target Bedtime=targetBT=10:30 PM=22.5

Sleep End Time=Wake Time=6:30 AM=6.5

Sleep End Time(adjusted for 24 hour periodicity)=24+6.5=30.5

Nighttime Sleep Midpoint=[(30.5−22.5)/2]modulus 24=2.5(relative to themidnight)

weight=nTST=5 hours=5.0

Nap Midpoint:

Sleep Start Time=NapStart=08:05 PM=20.08333

NapDuration=02 h05 m=2.083333

Sleep EndTime=NapEnd=NapStart+NapDuration=20.08333+2.083333=22.16667(10:10 PM)

Nap Midpoint=NapStart+(NapEnd−NapStart)/2=20.08333+

[(22.16667−20.08333)/2]−24=−2.875(relative to the midnight)

weight=NapDuration=2.083333

Weighting of Sleep Episodes

TST=sum(all sleep episodes)=sum(5.0, 2.083333)=7.083333

Weighted Nighttime Sleep=mid*(weight/TST)=2.5*(5/7.083333)=1.7647059

Weighted NapSleep=mid*(weight/TST)=−2.875*(2.083333/7.083333)=−0.8455882

Average of Weighted Sleep Episodes

Mean of(1.7647059, −0.8455882)=0.4595588

Correction for Target Bedtime

Correction Amount=24−targetBT=24−22.5=1.5

MoST=0.4595588+1.5=1.959559(relative to the target bedtime).

Under ideal circumstances in which an individual sleeps at their desiredtime for 7-8 hours and does not have any daytime naps the MoST will bearound 3.5-4.0. In the above hypothetical example, this individual had alate afternoon or night nap which pulls the midpoint below this desiredrange to 1.96. Alternatively, if a patient has more morning naps thenthis would potentially lead to a bigger number. If the illustration werechanged such that the hypothetical patient slept from 10:30 pm to 6:30am with no naps, then the patient's MoST would be 4.0. This algorithmdynamically takes into account the information from both the nighttimesleep as well as the daytime napping. Additionally, because the weightedsleep episodes are divided by the total number of sleep episodes withina 24 hour period the derived midpoint of sleep timing will be pushed to0 (and away from the optimal value of 3.5-4.0) as an individual's sleepbecomes more fragmented. An improvement in MoST is defined as anincrease in the MoST scale.

A useful clinical response scale (CRS or N24CRS) can be formed bycombining the results of all of LQ-nTST, UQ-dTSD, MoST and CGI-C. In anillustrative embodiment, each assessment on the scale is scored as a 1or 0 depending on whether the pre-specified threshold is achieved ornot, as defined in the table that follows. The score for each assessmentis summed with a range of 0-4. Individuals with a N24CRS score of ≧3 areclassified as having responded to treatment.

Non-24 Scale of Clinical Response

Assessment Threshold of response LQ-nTST >30, >40 or >45 minutesincrease in average nighttime sleep duration UQ-dTSD >30, >40, or >45minutes decrease in average daytime sleep duration MoST >20, >25 or >30minutes increase CGI-C <1 or <2 from baselineor any combination or permutation thereof. Increases and decreases induration, and other scores in the N24CRS, may be determined by comparingbaseline, which may be an average of two or more assessments, topost-treatment, which may be an average of two or more post-treatmentassessments. For example, the CGI-C scoring of <=1 (or <=2) can be acomparison of baseline score, which may be a single data point or anaverage of two (or more) scores from assessments taken prior to orshortly after initiation of treatment, to single data point or to anaverage of two (or more) scores from post-treatment assessments.

In an illustrative embodiment, improvement, i.e., response to treatment,is defined as the coincident demonstration of:

1. shift of tau towards 24 hours and

2. a score of >=3 on the above-described N24CRS.

In such embodiment, tau can be measured using any methodology includingbut not limited to aMT6 in urine, cortisol, melatonin in blood orsaliva, etc., substantially as described above.

A score of >=2 can also indicate improvement, i.e., patient response totreatment.

The data required to calculate parameters such as LQ-nTST, UQ-dTSD, andMoST, can be objectively quantified in sleep studies or, morepractically, it can be collected by way of patient questionnaires thatask patients to self-assess, e.g., did the patient sleep, what time didhe or she go to bed, how long did it take to fall asleep, etc. Incertain clinical studies, subjects will be required to call anInteractive Voice Response System (IVRS) twice a day starting the dayafter all screening assessments are completed and continue through therandomization phase for 2.5 circadian cycles or 6 months whichever isless. Subjects will call the IVRS twice, once in the morning no laterthan 1 hour after scheduled awakening to report nighttime sleepparameters (PSQ) and again in the evening no later than 15 minutes afterthe subjects daily dosing time to report the length and duration of anydaytime sleep episode(s) (PreSQ). The IVRS will automatically call backany subject that fails to perform the required calls within theallocated timeframe. One of skill in the art can readily transfer thisor similar methodologies to the treatment setting.

It will be appreciated, of course, that other methodologies may be usedto ascertain improvement following initiation of treatment or thatvariations in the above-described methodologies can be employed, e.g.,by utilizing other tau determination methods and/or by measuringdifferent or additional sleep parameters.

Illustrative efficacy indicators based on the above include, e.g.:

-   1. Combined sleep/wake response (>=90 minute increase in LQ-nTST    plus a 90 minute decrease in UQ-dTSD);-   2. Entrainment of cortisol secretion;-   3. Entrainment+45 minute increase in LQ-nTST;-   4. Entrainment+45 minute decrease in UQ-dTSD;-   5. Entrainment+>=30 minutes increase in MoST;-   6. Entrainment+a score of much improved or better on the CGI-C    scale;-   7. Increase in LQ-nTST;-   8. Decrease in UQ-dTSD;-   9. Improvement in MoST;-   10. Improvement in CGI-C;-   11. N24CRS=4;-   12. Combined sleep/wake response (>=45 minute increase in LQ-nTST    plus a 45 minute decrease in UQ-dTSD).

In carrying out these methods of the invention, the average of multiplepre-treatment and post-treatment assessments can be used to smooth outtest to test and/or day to day variability. For example, a baseline MoSTcan be compared to the average of two post-treatment initiation MoSTs;in this case, preferably, the difference between the two post-treatmentMoSTs is less than 2 hours. If the difference is greater than about 2hours, one or more further MoST assessments can be carried out.

If efficacy is shown, i.e., if a patient is determined to have achievedor to be moving in the direction of a normal circadian rhythm (i.e., 24hours or up to 24.1 hours), then treatment can be continued. If efficacyis not shown, then a physician or other healthcare worker may wish todiscontinue treatment or change the dose of the melatonin agonist, orotherwise alter the treatment method.

The above-described response assessment methodologies can also beutilized for diagnostic purposes. So, for example, a MoST of less thanabout 3.5, or less than about 3.0, or less than about 2.5 can be anindication that the patient is suffering from a free running circadianrhythm. Such diagnostic can employ one or more of the above-describedparameters optionally with other diagnostic markers also being assessed.For example, the patient's MoST score in combination with a taudetermination could also be or be part of a useful diagnostic for freerunning circadian rhythm.

Thus, in one method of treatment that comprises an aspect of thisinvention, a patient who presents himself or herself to a physician orother healthcare professional with symptoms of a sleep disorder, e.g.,difficulty sleeping at night, frequent daytime naps, etc., is firstdiagnosed by assessment of the patient's MoST, with or without otherdiagnostic assessments. Such patient who has a low, e.g., less than 3.5MoST is then treated with a melatonin agonist, e.g., tasimelteon.

In Phase III clinical trials, i.e., safety and efficacy studies inhumans, (SET Study), tasimelteon was demonstrated to be useful inentraining Non-24 patients to a 24 hour circadian rhythm. Specifically,patients were orally administered 20 mg tasimelteon per day for at least12 weeks prior to re-estimating tau. Patients were selected forrandomization or open label based on baseline tau estimates. Drug wasadministered at about 1 hour prior to target sleep time, as determinedby patients based on a 9 hour nighttime sleep period.

The SET study was an 84 patient randomized, double-masked,placebo-controlled study in patients with Non-24. The primary endpointsfor this study were Entrainment of the melatonin (aMT6s) rhythm to the24-hour clock and Clinical Response as measured by Entrainment plus ascore of greater than or equal to 3 on the following N24CRS:

Non-24 Scale of Clinical Response:

Assessment Threshold of response LQ-nTST >=45 minutes increase inaverage nighttime sleep duration UQ-dTSD >=45 minutes decrease inaverage daytime sleep duration MoST >20, >25 or >30 minutes increase anda standard deviation <=2 hours during double-masked phase CGI-C <=2.0from the average of Day 112 and Day 183 compared to baseline

A second study (RESET Study) was a 20 patient randomized withdrawalstudy designed to demonstrate the maintenance effect of 20 mg/daytasimelteon in the treatment of blind individuals with Non-24. Patientswere treated with tasimelteon for at least twelve weeks during anopen-label run-in phase during the SET Study. Patients who responded totasimelteon treatment during the run-in phase were then randomized toreceive either placebo or tasimelteon (20 mg/day) for 2 months.

Results relating to the primary endpoint of the SET Study are summarizedin Table 1A.

Table 1A. SET Study—Primary End Points Results:

Tasimelteon (%) Placebo (%) p-value Entrainment (aMT6s) 20.0 2.6 0.0171Clinical Response 23.7 0.0 0.0028 (Entrainment¹ + N24CRS >=3) ClinicalResponse2 28.9 0.0 0.0006 (Entrainment¹ + N24CRS >=2) N24CRS >=3² 28.92.9 0.0031 N24CRS >=2² 57.9 20.6 0.0014 NOTES: ¹Entrainment status fromthe randomized portion of the SET study and/or the screening portion ofthe RESET study ²Sensitivity Analysis

The SET study also assessed a number of secondary endpoints includingEntrainment of cortisol rhythm and a broad range of clinical sleep andwake parameters. These parameters included improvement in the totalnighttime sleep in the worst 25% of nights (LQ-nTST), decrease in thetotal daytime sleep duration in the worst 25% of days (UQ-dTSD) andmidpoint of sleep timing (MoST) which is derived from a combination ofthe sleep reported for both nighttime and daytime. CGI-C is aseven-point rating scale of global functioning with lower scoresindicating larger improvements.

TABLE 1B SET Study - Secondary Endpoints Results Tasimelteon Placebop-value Entrainment (cortisol) (%) 17.5 2.6 0.0313 N24CRS (LS meanminutes) 1.77 0.67 0.0004 CGI-C¹ (LS mean minutes) 2.6 3.4 0.0093LQ-nTST and UQ-dTSD >=90 min² 23.8 4.5 0.0767 (%) LQ-nTST andUQ-dTSD >=45 min³ 31.6 8.8 0.0177 (%) LQ-nTST (LS mean minutes) 57.016.8 0.0055 UQ-dTSD¹ (LS mean minutes) −46.2 −18.0 0.0050 MoST (LS meanminutes) 34.8 14.4 0.0123 NOTES: ¹For CGI-C and UQ-dTSD smaller numbersindicate improvement. ²For this endpoint, only subjects with significantsleep and nap problems at baseline were included. ³Sensitivity Analysis

The percentage of patients entrained was higher among patients on drugfor two complete circadian cycles. It was also higher among patients nottaking a beta blocker and lower among patients with very long tau, e.g.,tau>=24.7. Among patients on drug for at least two circadian cycles, noton beta blockers, and tau<24.7 hours, the percentage of entrainedpatients was approximately 85%.

The results of the SET study represent the initial data from thetasimelteon Non-24 Phase III development program and demonstrate themultiple benefits of this novel therapy in treating patients sufferingfrom this rare circadian rhythm disorder. In the SET study, tasimelteonwas demonstrated to be safe and well tolerated.

The primary endpoint of the RESET Study was the maintenance of effect asmeasured by entrainment of the melatonin (aMT6s) rhythm. Resultsrelating to the primary endpoint of the RESET Study are summarized inTable 2A.

TABLE 2A RESET Study - Primary Endpoint Results: Tasimelteon Placebop-value Maintenance of entrainment (aMT6s) 90.0 20.0 0.0026 (%)The RESET study also assessed a number of secondary endpoints includingmaintenance of entrainment of the cortisol rhythm and a range of sleepand wake parameters including LQ-nTST (total nighttime sleep in theworst 25% of nights), UQ-dTSD (total daytime sleep duration in the worst25% of days) and MoST (midpoint of sleep timing from both nighttime anddaytime sleep). Results relating to the secondary endpoints of the RESETStudy are summarized in Table 2B.

TABLE 2B RESET Study - Secondary Endpoints Results: p- TasimelteonPlacebo Difference value maintenance of 80.0 20.0 60.0 0.0118entrainment (cortisol) (%) LQ-nTST −6.6 −73.8 67.2 0.0233 (LS meanminutes)¹ UQ-dTSD −9.6 49.8 −59.4 0.0266 (LS mean minutes)² MoST 19.8−16.2 36.0 0.0108 (LS mean minutes)¹ NOTES: ¹Higher number indicatesimprovement ²Lower number indicates improvement

From the run-in phase of the study, the rate of entrainment amongtasimelteon treated patients ranged from 50% to 85% based on individualpatient characteristics. In a time to relapse analysis (45 min decrementof weekly average nighttime sleep), placebo treated patients relapsed inhigher numbers and at an earlier time than tasimelteon treated patients(P=0.0907).

The RESET study demonstrates the efficacy of chronic treatment withtasimelteon in Non-24 and further supports the results of the SET study,which established the ability of tasimelteon to entrain the master bodyclock and significantly improve the clinical symptoms of Non-24.

For maintenance of an entrained circadian rhythm, i.e., chronictreatment, the treatment regimens described herein can be continueddaily indefinitely. So, for example, tasimelteon can be administeredorally, e.g., at a dose of 20 mg/day, e.g., at about ½ to about 1 hourprior to bedtime.

Results of clinicalstudy also show a strong correlation betweenendogenous melatonin and efficacy of tasimelteon in entraining patientsto a 24 hour circadian rhythm. The following table (Table 3A) comparesthe peak aMT6s levels in the 24 entrained and 23 non-entrained patients.

TABLE 3A Peak aMT6s (ng/hr) Peak aMT6s (ng/hr) Entrained PatientsNon-entrained Patients 291.05 261.68 302.40 334.34 350.92 409.12 362.07472.99 510.60 514.14 786.85 552.77 811.80 552.90 958.89 581.95 1102.76810.43 1205.45 846.55 1329.08 862.91 1442.48 1155.66 1502.80 1284.352106.44 1295.37 2211.81 1397.71 2226.06 1444.94 2287.07 1451.43 2566.271622.23 2706.67 1637.45 2801.31 1719.94 2891.17 1749.32 3391.00 2329.653867.45 2671.17 5547.22

The average baseline aMT6s excretion rate in urine, as determined usingthe methodology described above, was 1814.98 ng/hr in subjects whobecame entrained in response to tasimelteon therapy and 1128.65 ng/hr insubjects who did not become entrained in response to tasimelteontherapy. Eleven of thirteen patients with a baseline aMT6s excretionrate >2000 ng/hr responded to therapy. See, Table 3B.

TABLE 3B Peak aMT6s (ng/hr) All <1500 ≧1500 <2000 ≧2000 Total 47 29 1834 13 Entrained 24 (51%) 12 (41%) 12 (67%) 13 (38%) 11 (85%) Non- 23(49%) 17 (59%)  6 (33%) 21 (62%)  2 (15%) entrained

Data from these studies currently available also indicate that betablocker therapy is indirectly related to efficacy of tasimelteon, i.e.,patients receiving beta blocker therapy were less likely to becomeentrained than patients who were not.

TABLE 4 Status Taking Beta Blocker Entrained Non-entrained No 24 19 Yes0 4

In addition, currently available data indicate a correlation between tauas determined by assaying for aMT6s levels in urine substantially asdescribed above and assaying for cortisol in urine substantially asdescribed above, as shown in Table 5.

TABLE 5 Cycle Cycle Tau CI Length Tau CI Length P Site # Subject #(aMT6s) CI Low High (Days) (Cortisol) CI Low High (Days) Value 405 300123.92 23.71 24.13 N/A 23.88 23.49 24.27 n/a 0.32 410 3002 24.02 23.8624.19 N/A 23.92 23.64 24.21 N/A 0.37 409 3003 23.97 23.77 24.17 N/A23.94 23.75 24.12 N/A 0.37 405 3002 23.98 23.86 24.1 N/A 23.96 23.824.13 n/a 0.46 405 3003 23.95 23.87 24.04 N/A 23.97 23.78 24.15 n/a 0.51424 3003 23.96 23.8 24.12 N/A 23.99 23.92 24.05 N/A 0.46 411 3001 24.0223.77 24.26 1482 24.01 23.48 24.54 2728 0.95 426 3002 24.01 23.87 24.153959 24.01 23.54 24.48 3111 0.95 410 3001 24.02 23.99 24.05 N/A 24.0223.89 24.15 1176 0.57 412 3002 23.99 23.88 24.09 N/A 24.05 23.09 25.02468 0.84 412 3003 23.98 23.88 24.08 N/A 24.05 23.84 24.26 460 0.4  4093002 24.08 23.99 24.17 290 24.08 23.95 24.21 287 0.11 424 3001 23.9723.68 24.26 N/A 24.17 24.02 24.32 140 0.04 407 3003 24.33 24.21 24.44 7424.11 23.97 24.24 225 0.08 410 3006 24.29 23.57 25.02 83 24.12 23.6524.58 205 0.39 407 3001 24.56 24.37 24.75 43 24.13 22.89 25.37 179 0.69401 3002 24.31 24.22 24.4 77 24.15 24.08 24.23 158 0.01 406 3002 24.4122.66 26.16 59 24.3 24 24.6 81 0.05 421 3001 24.86 22.57 27.14 29 24.3721.83 26.92 65 0.31 406 3003 24.48 24.07 24.9 50 24.42 24.25 24.59 580.01 410 3004 24.39 24.27 24.51 62 24.43 24.4 24.47 56 0.01 403 300124.76 23.42 26.1 32 24.44 24.06 24.82 55 0.04 419 3001 25.28 25.04 25.5119 24.54 24.07 25.02 45 0.04 409 3001 24.52 24.41 24.63 47 24.58 24.4724.68 42 0.01 411 3003 24.5 24.13 24.87 49 24.61 24.28 24.94 40 0.02 4113004 24.92 24.46 25.38 27 24.74 24.15 25.34 33 0.03 403 3002 24.8 24.5925.01 31 24.77 23.94 25.6 32 0.06 425 3003 24.77 23.67 25.88 32 24.8623.91 25.81 29 0.06 425 3002 25.01 24.63 25.4 24 25.1 24.65 25.55 220.01

Data from clinical studies also show that CYP1A2 inhibitors and smokingboth affect patient exposure to drug.

Fluvoxamine is a strong CYP1A2 inhibitor. AUC_(0-inf) for tasimelteonincreased approximately 7-fold, and the C_(max) increased approximately2-fold upon co-administration of fluvoxamine and tasimelteon, comparedto tasimelteon administered alone.

Table 6 below shows the effect of co-administration of tasimelteon andfluvoxamine on tasimelteon's pharmacokinetics. Twenty-four healthy maleor female subjects between the ages of 18 and 55 years of age(inclusive) who were non-smokers with a body mass index (BMI) of 18 and35 kg/m2 participated in this open-label, single-sequence studyconducted at one site. On day 1, subjects were administered 5.667 mg oftasimelteon. On days 2-7, subjects were administered 50 mg offluvoxamine. On day 8, subjects were co-administered 5.667 mg oftasimelteon and 50 mg of fluvoxamine.

TABLE 6 Tmax AUC (inf) CL/F Analyte Day Cmax (ng/ml) (h) (h × ng/mL) t½(h) (mL/min) Tasimelteon 1 68.0 ± 28.9 0.50 102 ± 61.5 1.20 ± 0.22 107 ±555 Tasimelteon 8  155 ± 51.1 0.50 701 ± 402  2.59 ± 0.71 189 ± 155Geometric Mean 232.74  N/A 653.36 211.82 15.31 Ratio* (%) M12 1 31.0 ±7.23 0.88 189 ± 90.8 3.03 ± 1.02 N/A M12 8 30.8 ± 17.6 3.00  435 ± 109.37.03 ± 3.27 N/A Geometric Mean 92.74 N/A 274.81 241.02 N/A Ratio (%) M131 87.5 ± 24.4 0.50 106 ± 32.6 1.00 ± 0.30 N/A M13 8 63.6 ± 24.6 0.50 133± 32.9 3.51 ± 1.18 Geometric Mean 69.31 N/A 125.05 349.81 N/A Ratio (%)*M9 1 67.6 ± 19.1 0.50 104 ± 30.0 1.14 ± 0.29 N/A M9 8 47.4 ± 24.2 0.75126 ± 29.6 3.83 ± 1.34 N/A Geometric Mean 64.94 N/A 122.56 328.02 N/ARatio (%)* M11 1 15.8 ± 5.40 1.00 44.5 ± 17.2 1.61 ± 0.55 N/A M11 8 11.0± 3.94 1.00 55.8 ± 18.3 4.14 ± 1.44 N/A Geometric Mean 68.71 N/A 126.03248.35 N/A Ratio (%)* M14 1 1.20 ± 0.40 0.75 4.54 ± 2.39  2.18 ± 0.97N/A M14 8 3.20 ± 1.49 4.00 42.6 ± 27.3  4.98 ± 1.89 N/A Geometric Mean264.58 N/A 944.73 243.34 N/A Ratio (%)*

FIG. 5 shows a diagram of a metabolic pathway of tasimelteon. FIGS. 6-11show plots of the effect of co-administration of tasimelteon andfluvoxamine on the concentration of, respectively, tasimelteon, the M9metabolite, the M11 metabolite, the M12 metabolite, the M13 metabolite,and the M14 metabolite. As can be seen from FIGS. 6-11, the increase inconcentration attributable to fluvoxamine co-administration was morepronounced with respect to tasimelteon and its primary metabolites (M12,M13, M14) than its secondary metabolites (M9, M11).

Table 7 below shows the effect of smoking on the concentration oftasimelteon and several of its metabolites. Smokers were defined asthose smoking 10 or more cigarettes per day. Non-smokers were defined asthose smoking no cigarettes per day.

TABLE 7 Cmax Tmax AUC (inf) CL/F Analyte Group (ng/ml) (h) (h × ng/mL)t½ (h) (mL/min) Vz/F (L) Tasimelteon Smokers  136 ± 59.5 0.75 205 ± 1520.99 ± 0.18 2,290 ± 1,232 189 ± 94.2 Tasimelteon Non- 239 ± 177 0.50 389± 429 1.18 ± 0.46 1,482 ± 1,008 133 ± 83.0 Smokers Geometric 63.98 N/A60.14 86.84 166.27 144.39 Mean Ratio* (%) M12 Smokers 123 ± 28  1.00 526± 193 2.11 ± 0.67 N/A N/A M12 Non- 108 ± 29  1.00 679 ± 433 3.05 ± 1.73N/A N/A Smokers Geometric 115.53 N/A 84.87 73.31 N/A N/A Mean Ratio (%)M13 Smokers 272 ± 86  0.75 329 ± 99  0.89 ± 0.26 N/A N/A M13 Non- 270 ±71  0.50 337 ± 94  1.18 ± 0.50 N/A Smokers Geometric 99.49 N/A 97.3177.51 N/A N/A Mean Ratio (%)* M9 Smokers 230 ± 118 0.75 315 ± 112 1.15 ±0.17 N/A N/A M9 Non-  279 ± 82.8 0.75 406 ± 75  1.38 ± 0.45 N/A N/ASmokers Geometric 77.18 N/A 74.36 85.40 N/A N/A Mean Ratio (%)* M11Smokers 46.17 ± 11.9  1.00 124 ± 42  1.99 ± 0.85 N/A N/A M11 Non- 54.9 ±15.1 1.00 154 ± 58  2.14 ± 0.94 N/A N/A Smokers Geometric 84.50 N/A81.84 94.13 N/A N/A Mean Ratio (%)* M14 Smokers 3.72 ± 1.86 0.75  9.45 ±11.88 1.13 ± 0.54 N/A N/A M14 Non- 6.18 ± 3.15 0.75 22.0 ± 24.2 1.84 ±1.22 N/A N/A Smokers Geometric 60.17 N/A 42.98 65.09 N/A N/A Mean Ratio(%)* M3 Smokers  177 ± 71.6 0.50  239 ± 44.4 3.48 ± 2.53 N/A N/A M3 Non- 135 ± 49.5 0.63  194 ± 64.6 4.00 ± 2.48 N/A N/A Smokers Geometric131.27  N/A 129.43  89.16 N/A N/A Mean Ratio (%)*

FIGS. 12-17 show plots of the effect of smoking on the concentration of,respectively, tasimelteon, the M9 metabolite, the M11 metabolite, theM12 metabolite, the M13 metabolite, and the M14 metabolite.

Related aspects of this invention include computer-based systemscomprising means for receiving data concerning treatment-related healthinformation, optionally transiently or indefinitely storing suchinformation, and directly or indirectly transmitting such information tosuch healthcare professional or patient. Such health information caninclude whether or not a patient is receiving, i.e., being treated with,a CYP1A2 inhibitor, information relating to a patient's endogenousmelatonin levels, information relating to a patient's endogenouscortisol levels, information relating to a patient's tau, informationrelating to whether or not a patient is receiving, i.e., being treatedwith, a beta blocker, information relating to whether or not the patientis a smoker, etc.

Accordingly, computer implemented systems and methods using the methodsdescribed herein are provided.

For example, related to this invention is a method comprising screeningpatient test samples to determine melatonin levels, collecting the data,and providing the data to a patient, a health care provider or a healthcare manager for making a conclusion based on review or analysis of thedata. In one embodiment the conclusion is provided to a patient, ahealth care provider or a health care manager includes transmission ofthe data over a network.

Melatonin level and circadian rhythm information or other patientspecific information such as recited above and as described herein, maybe stored in a computer readable form. Such information can alsoinclude, e.g., one or more of whether or not a patient is being treatedwith a CYP1A2 inhibitor, information relating to a patient's endogenousmelatonin levels, information relating to a patient's endogenouscortisol levels, information relating to a patient's tau, informationrelating to whether or not a patient is receiving, i.e., being treatedwith, a beta blocker, information relating to whether or not the patientis a smoker, etc. Such a computer system typically comprises majorsubsystems such as a central processor, a system memory (typically RAM),an input/output (I/O) controller, an external device such as a displayscreen via a display adapter, serial ports, a keyboard, a fixed diskdrive via a storage interface and optionally, a disk drive operative toreceive a floppy disc, a CD or DVD, or any other data storage medium.Many other devices can be connected, such as a closed or open networkinterface.

The computer system may be linked to a network, comprising a pluralityof computing devices linked via a data link, such as a cable, telephoneline, ISDN line, wireless network, optical fiber, or other suitablesignal transmission medium, whereby at least one network device (e.g.,computer, disk array, etc.) comprises a pattern of magnetic domains(e.g., magnetic disk) and/or charge domains (e.g., an array of DRAMcells) composing a bit pattern encoding data acquired from an assay ofthe invention.

The computer system can comprise code for interpreting the results oftau analyses as described herein. Thus in an exemplary embodiment, thedetermination of peak melatonin levels (or surrogate) and of tau resultsare provided to a computer where a central processor executes a computerprogram for determining, e.g., optimal initiation of treatment times,the likelihood of response to treatment, etc.

Also related to this invention is use of a computer system, such as thatdescribed above, which comprises: (1) a computer including a computerprocessor; (2) a stored bit pattern encoding the results obtained by themelatonin analyses of the invention, which may be stored in thecomputer; (3) and, optionally, (4) a program for determining thelikelihood of a therapeutic response.

A computer-based system for use in the methods described hereingenerally includes at least one computer processor (e.g., where themethod is carried out in its entirety at a single site) or at least twonetworked computer processors (e.g., where data is to be input by a user(also referred to herein as a “client”) and transmitted to a remote siteto a second computer processor for analysis, where the first and secondcomputer processors are connected by a network, e.g., via an intranet orinternet). The system can also include a user component(s) for input;and a reviewer component(s) for review of data, generated reports, andmanual intervention. Additional components of the system can include aserver component(s); and a database(s) for storing data (e.g., as in adatabase of report elements, e.g., interpretive report elements, or arelational database (RDB) which can include data input by the user anddata output. The computer processors can be processors that aretypically found in personal desktop computers (e.g., IBM, Dell,Macintosh), portable computers, mainframes, minicomputers, or othercomputing devices.

Illustrative reports which can be displayed or projected, or printed,are provided in FIGS. 1, 2, 3, and 4.

A networked client/server architecture can be selected as desired, andcan be, for example, a classic two or three tier client server model. Arelational database management system (RDMS), either as part of anapplication server component or as a separate component (RDB machine)provides the interface to the database.

In one example, the architecture is provided as a database-centricclient/server architecture, in which the client application generallyrequests services from the application server which makes requests tothe database (or the database server) to populate the report with thevarious report elements as required, particularly the interpretivereport elements, especially the interpretation text and alerts. Theserver(s) (e.g., either as part of the application server machine or aseparate RDB/relational database machine) responds to the client'srequests.

The input client components can be complete, stand-alone personalcomputers offering a full range of power and features to runapplications. The client component usually operates under any desiredoperating system and includes a communication element (e.g., a modem orother hardware for connecting to a network), one or more input devices(e.g., a keyboard, mouse, keypad, or other device used to transferinformation or commands), a storage element (e.g., a hard drive or othercomputer-readable, computer-writable storage medium), and a displayelement (e.g., a monitor, television, LCD, LED, or other display devicethat conveys information to the user). The user enters input commandsinto the computer processor through an input device. Generally, the userinterface is a graphical user interface (GUI) written for web browserapplications.

The server component(s) can be a personal computer, a minicomputer, or amainframe and offers data management, information sharing betweenclients, network administration and security. The application and anydatabases used can be on the same or different servers.

Other computing arrangements for the client and server(s), includingprocessing on a single machine such as a mainframe, a collection ofmachines, or other suitable configuration are contemplated. In general,the client and server machines work together to accomplish theprocessing of the present invention.

Where used, the database(s) is usually connected to the database servercomponent and can be any device which will hold data. For example, thedatabase can be any magnetic or optical storing device for a computer(e.g., CDROM, internal hard drive, tape drive). The database can belocated remote to the server component (with access via a network,modem, etc.) or locally to the server component.

Where used in the system and methods, the database can be a relationaldatabase that is organized and accessed according to relationshipsbetween data items. The relational database is generally composed of aplurality of tables (entities). The rows of a table represent records(collections of information about separate items) and the columnsrepresent fields (particular attributes of a record). In its simplestconception, the relational database is a collection of data entries that“relate” to each other through at least one common field.

Additional workstations equipped with computers and printers may be usedat point of service to enter data and, in some embodiments, generateappropriate reports, if desired. The computer(s) can have a shortcut(e.g., on the desktop) to launch the application to facilitateinitiation of data entry, transmission, analysis, report receipt, etc.as desired.

The present invention also contemplates a computer-readable storagemedium (e.g. CD-ROM, memory key, flash memory card, diskette, etc.)having stored thereon a program which, when executed in a computingenvironment, provides for implementation of algorithms to carry out allor a portion of the results of a response likelihood assessment asdescribed herein. Where the computer-readable medium contains a completeprogram for carrying out the methods described herein, the programincludes program instructions for collecting, analyzing and generatingoutput, and generally includes computer readable code devices forinteracting with a user as described herein, processing that data inconjunction with analytical information, and generating unique printedor electronic media for that user.

Where the storage medium provides a program that provides forimplementation of a portion of the methods described herein (e.g., theuser-side aspect of the methods (e.g., data input, report receiptcapabilities, etc.)), the program provides for transmission of datainput by the user (e.g., via the internet, via an intranet, etc.) to acomputing environment at a remote site. Processing or completion ofprocessing of the data is carried out at the remote site to generate areport. After review of the report, and completion of any needed manualintervention, to provide a complete report, the complete report is thentransmitted back to the user as an electronic document or printeddocument (e.g., fax or mailed paper report). The storage mediumcontaining a program according to the invention can be packaged withinstructions (e.g., for program installation, use, etc.) recorded on asuitable substrate or a web address where such instructions may beobtained.

The computer-readable storage medium can also be provided in combinationwith one or more reagents for carrying out response likelihoodassessment.

Also related to this invention are methods of generating a report basedon the analyses of melatonin levels in a patient suffering from Non-24.In general, such method can comprise the steps of determininginformation indicative of the levels of endogenous melatonin, in abiological sample; and creating a report summarizing said information,such as by reporting whether or not a patient is being treated with aCYP1A2 inhibitor, with or without additional information. In oneillustrative embodiment of the method, said report includes one or moreof an indication of whether or not a patient's melatonin levels achievea Threshold Concentration, an indication of the patient's cortisollevels, an indication of the patient's tau, an indication of whether ornot the patient is being treated with a CYP1A2 inhibitor, informationrelating to whether or not the patient is a smoker, and an indication ofwhether or not the patient is being treated with an agent that reducesendogenous melatonin such as a beta blocker.

In some embodiments, the report includes a Threshold Concentration and,optionally, the peak melatonin concentration in the patient's biologicalsample. In some embodiments, the report includes information relating tothe co-administration of tasimelteon and a CYP1A2 inhibitor, such asinformation relating to increased exposure to tasimelteon that mayensue, information related reducing the dose of tasimelteon or of theCYP1A2 inhibitor, information relating to heightened monitoring, etc. Insome embodiments, the report includes information relating to theadministration of tasimelteon and smoking, such as information relatedto decreased exposure to tasimelteon that may ensue, informationrelating to increasing the dose of tasimelteon, information related tomonitoring for levels of tasimelteon in the blood, etc.

Such report can further include one or more of: 1) information regardingthe testing facility; 2) service provider information; 3) patient data;4) sample data; 5) an interpretive report, which can include variousinformation including: a) indication; b) test data, and 6) otherfeatures.

In some embodiments, the report further includes a recommendation for atreatment modality for said patient. In such aspect, the report mayinclude information to support a treatment recommendation for saidpatient, e.g., a recommendation for non-treatment with a melatoninagonist or for heightened monitoring. In all aspects, the report mayinclude a classification of a subject into a group, e.g., likelynon-responders or likely responders.

In some embodiments, the report is in electronic form e.g., presented onan electronic display (e.g., computer monitor).

In some embodiments, the report is a visual report comprising:

1) a descriptive title

2) a patient identifier

3) the patient's target initiation of sleep time and one or more of:

(i) a graph of rate of production of melatonin or melatonin surrogateversus time for each Collection Session, the graph showing data pointsand the calculated circadian cycle including acrophase, each graph beingannotated with the projected acrophase and Standard Error,

(ii) a graph of acrophase (time of day) vs. Day showing the projectedacrophase determined for each Collection Session and the slopedetermined by linear regression analysis of the projected acrophasetimes, said graph being annotated with the length of the patient's tau,the Standard Error and the Confidence Interval expressed both as a pvalue and as a range of hours, and

(iii) an acrophase table showing the projected time of acrophase for 90days following the end of the last Collection Session, said tabledifferentially highlighting the date and time of the projected acrophaseclosest to the target acrophase, the optimal day for initiation oftreatment and an estimated window for initiation of treatment.

Such illustrative report is provided in FIG. 1 for a subject that is notsuffering Non-24 and in FIG. 2 for a patient that is suffering fromN24SWD.

A person or entity who prepares a report (“report generator”) may alsoperform the likelihood assessment. The report generator may also performone or more of sample gathering, sample processing, and data generation,e.g., the report generator may also perform one or more of: a) samplegathering; b) sample processing; c) measuring melatonin or melatoninsurrogate levels. Alternatively, an entity other than the reportgenerator can perform one or more sample gathering, sample processing,and data generation.

For clarity, it should be noted that the term “user,” which is usedinterchangeably with “client,” is meant to refer to a person or entityto whom a report is transmitted, and may be the same person or entitywho does one or more of the following: a) collects a sample; b)processes a sample; c) provides a sample or a processed sample; and d)generates data for use in the likelihood assessment. In some cases, theperson(s) or entity(ies) who provides sample collection and/or sampleprocessing and/or data generation, and the person who receives theresults and/or report may be different persons, but are both referred toas “users” or “clients” herein to avoid confusion. In certainembodiments, e.g., where the methods are completely executed on a singlecomputer, the user or client provides for data input and review of dataoutput. A “user” can be a health professional (e.g., a clinician, alaboratory technician, a physician, etc.).

In embodiments where the user only executes a portion of the method, theindividual who, after computerized data processing according to themethods of the invention, reviews data output (e.g., results prior torelease to provide a complete report, a complete, or reviews an“incomplete” report and provides for manual intervention and completionof an interpretive report) is referred to herein as a “reviewer.” Thereviewer may be located at a location remote to the user (e.g., at aservice provided separate from a healthcare facility where a user may belocated).

Where government regulations or other restrictions apply (e.g.,requirements by health, malpractice or liability insurance, or policy),results, whether generated wholly or partially electronically, aresubjected to a quality control routine prior to release to the user.

In another aspect, the present disclosure concerns methods of preparinga personalized pharmacologic profile for a patient by a) determining thepatient's levels of endogenous melatonin or melatonin surrogate; and (b)creating a report summarizing the data and/or compiling such data withother data relevant to understanding the patient's specificpharmacologic characteristics and condition.

In accordance with the method of this invention, the dosage oftasimelteon to be administered will depend on various factors such asthe characteristics of the subject being treated, e.g., the severity ofdisorder, responsiveness to melatonin agonists, age, weight, health,types of concurrent treatment, if any, etc.

The above described computer-implemented methods, systems, reports,etc., can also be applied to determination of efficacy of treatment,such as but not limited to the efficacy determination methodologiesdescribed above. For example, computer-based systems can be used torecord and report information relating to one or more of MoST, LQ-nTST,UQ-dTSD and CGI-C and/or to tau determinations made prior to or shortlyafter initiation of therapy as well as subsequent tau determinations.

By way of further illustration, related aspects of this inventioninclude computer-based systems comprising means for receiving dataconcerning one or more of MoST, LQ-nTST, UQ-dTSD and CGI-C and/or to taudeterminations made prior to or shortly after initiation of therapy aswell as subsequent tau determinations;

a method comprising collecting data relating to one or more of MoST,LQ-nTST, UQ-dTSD and CGI-C and/or to tau determinations made prior to orshortly after initiation of therapy as well as subsequent taudeterminations and providing the data to a patient, a health careprovider or a health care manager for making a conclusion based onreview or analysis of the data. In one embodiment the conclusion isprovided to a patient, a health care provider or a health care managerincludes transmission of the data over a network;

information relating to one or more of MoST, LQ-nTST, UQ-dTSD and CGI-Cand/or to tau determinations made prior to or shortly after initiationof therapy as well as subsequent tau determinations stored in a computerreadable form;

a computer system as described above for receiving, storing andoutputting such information, optionally linked to a network andoptionally comprising code for interpreting the results of efficacyassessment(s) as described herein;

a computer-readable storage medium (e.g., CD-ROM, memory key, flashmemory card, diskette, etc.) having stored thereon a program which, whenexecuted in a computing environment, provides for implementation ofalgorithms to carry out all or a portion of the analysis of efficacyassessments as described herein;

methods of generating a report based on the efficacy assessments asdescribed herein, e.g., a report that includes one or more of anindication of whether or not a patient is responding to therapy.

Such information, databases, systems, methods, analyses, reports,profiles, outputs, recommendations, etc., can be incorporated intostorage media, computer systems, and networks, such as are describedhereinabove with respect to other parameters, e.g., melatonin levels,circadian rhythms, cortisol levels, tau, co-treatment with CYP1A2inhibitors, co-treatment with a beta blocker, and smoking, with orwithout information relating to some or all of such other parameters.

An effective dose is one that over a period of time of treatment, whichmay be, e.g., 1 day or multiple weeks, results in entrainment of thepatient to a 24 hour circadian rhythm. Patients whose tau is reduced to24 hours, e.g., <24.1 hrs, with a 95% confidence interval that includes24.0 can be considered to have been entrained, although other values canalso be used to define successful entrainment.

The daily dose of tasimelteon useful in entraining patients with Non-24to a 24 hour circadian rhythm will, in general, be in the range of about1 to about 100 mg, e.g., about 10 to about 100 or about 20 to about 50.A dose of 20 mg is typically sufficient, in particular, for individualswho are not also being administered a CYP1A2 inhibitor or a beta blockeror who are not smokers.

Similar doses may be employed when entraining a patient's cortisolcircadian rhythm.

As discussed above, it has been found that co-administration oftasimelteon with CYP1A2 inhibitors unexpectedly increases theconcentration of tasimelteon. This is likely a consequence of inhibitionof CYP1A2-mediated conversion of tasimelteon to a metabolite.

CYP1A2 inhibitors include, for example, fluoroquinolone antibiotics,such as ciprofloxacin, SSRIs such as fluvoxamine, and calcium channelblockers such as verapamil. Accordingly, in the case that a patient isto be administered a dose of tasimelteon as part of an attempt toentrain the patient to a 24-hour circadian rhythm and that patient isalso being treated with a CYP1A2 inhibitor, it may be necessary ordesirable to reduce the dose of tasimelteon, the dose of the CYP1A2inhibitor, or both. Alternatively, or in addition, it may be necessaryor desirable to monitor the patient's plasma concentration oftasimelteon or monitor the patient for an adverse reaction associatedwith tasimelteon.

For example, the dose of tasimelteon administered to a patient alsobeing treated with a CYP1A2 inhibitor may be reduced to less than 20 mgper day, e.g., about 15 to about 19 mg per day, about 10 to about mg perday, or about 5 to about 10 mg per day, e.g., 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, or 19 mg/day. In some cases, the dose oftasimelteon or the dose of the CYP1A2 inhibitor may be reduced to zero.In an embodiment of the invention, tasimelteon is not be used incombination with fluvoxamine. Other less strong CYP1A2 inhibitors havenot been adequately studied. Tasimelteon should be administered withcaution to patients taking less strong CYP1A2 inhibitors.

Aspects of the invention, as they relate to the effects of a CYP1A2inhibitor on tasimelteon exposure, include, without limitation, thefollowing:

treating a patient with tasimelteon wherein the patient is also beingtreated with a CYP1A2 inhibitor, said method comprising one or more ofthe following: reducing the dose of tasimelteon, reducing the dose ofthe CYP1A2 inhibitor, monitoring the patient's plasma concentration oftasimelteon, or monitoring the patient for an adverse reactionassociated with tasimelteon;

treating a patient with tasimelteon wherein the patient is also beingtreated with a substance that is a known inhibitor of CYP1A2, saidmethod comprising monitoring the patient for a potential or actualadverse event associated with increased plasma concentration oftasimelteon while the patient is being coadministered tasimelteon andthe CYP1A2 inhibitor;

treating a patient suffering from a sleep disorder wherein such patientis being treated with a CYP1A2 inhibitor, the method comprising:internally administering tasimelteon to the patient in a reduced amountrelative to an amount that would be administered to a patient sufferingfrom a sleep disorder but not being treated with a CYP1A2 inhibitor;

a computing device having a processor; a storage device containinginformation that the patient is being treated with a CYP1A2 inhibitor;an input device for inputting to either or both of the computing deviceor the storage device information that the patient will be prescribed adose of tasimelteon; a computer program operable retrieve from thestorage device the information that the patient is being treated with aCYP1A2 inhibitor upon inputting the information that the patient will beprescribed the dose of tasimelteon; and an output device for outputtingto a user the information that the patient is being treated with aCYP1A2 inhibitor;

a computer-implemented method of treating a patient suffering from asleep disorder, the method comprising: entering into an electronicdatabase information related to the treatment of a patient withtasimelteon; searching, using a computing device, a medical record ofthe patient for information related to the current treatment of thepatient with an agent other than tasimelteon; and determining, using thecomputing device, whether the agent other than tasimelteon is a CYP1A2inhibitor;

a pharmaceutical composition for the treatment of a sleep disorder in anindividual being treated with a CYP1A2 inhibitor, the compositioncomprising: a pharmaceutically-acceptable carrier; and a quantity oftasimelteon corresponding to a daily dosage of less than 20 mg.

In another embodiment, patients who are receiving a CYP1A2 inhibitor,e.g., fluvoxamine, are not treated with tasimelteon. In a relatedembodiment, patients are instructed not to receive, and healthcareproviders are instructed not to prescribe, tasimelteon if the patient isalready receiving a CYP1A2 inhibitor, e.g., fluvoxamine.

Smoking, on the other hand, has been found to increase the clearance oftasimelteon, thereby reducing patient exposure. Accordingly,administration of tasimelteon or a tasimelteon metabolite to anindividual who smokes may, in some cases, require increasing the dose oftasimelteon or tasimelteon metabolite and/or reducing or eliminating theindividual's smoking.

Accordingly, in the case that a patient is to be administered a dose oftasimelteon as part of an attempt to entrain the patient to a 24-hourcircadian rhythm and that patient is also a smoker, it may be necessaryor desirable to increase the dose of tasimelteon. Alternatively, or inaddition, it may be necessary or desirable to monitor the patient'splasma concentration of tasimelteon.

For example, the dose of tasimelteon administered to a patient who alsosmokes may be increased to greater than 20 mg per day, e.g., 25 mg perday, 30 mg per day, 40 mg per day, 50 mg per day or even 100 mg per day.

Aspects of the invention, as they relate to the effects of smoking ontasimelteon exposure, include, without limitation, the following:

treating a patient with tasimelteon wherein the patient is a smoker,said method comprising one or more of the following: increasing a doseof tasimelteon, monitoring the patient's blood levels of tasimelteon,and instructing the patient to reduce or eliminate smoking;

treating a patient suffering from a sleep disorder wherein such patientis a smoker, the method comprising: internally administering tasimelteonto the patient in an increased amount relative to an amount that wouldbe administered to a patient suffering from a sleep disorder who is nota smoker;

a system comprising: at least one computing device having a processor; astorage device containing information that the patient is a smoker; aninput device for inputting to either or both of the computing device orthe storage device information that the patient will be prescribed adose of tasimelteon; a computer program operable retrieve from thestorage device the information that the patient is a smoker uponinputting the information that the patient will be prescribed the doseof tasimelteon; and an output device for outputting to a user theinformation that the patient is a smoker;

a computer-implemented method of treating a patient suffering from asleep disorder, the method comprising: entering into an electronicdatabase information related to the treatment of a patient withtasimelteon; searching, using a computing device, a medical record ofthe patient for information related to whether the patient is a smoker;and determining, using the computing device, whether the patient is asmoker;

a pharmaceutical composition for the treatment of a sleep disorder in anindividual who smokes, the composition comprising: apharmaceutically-acceptable carrier; and a quantity of tasimelteoncorresponding to a daily dosage of greater than 20 mg.

In general, the melatonin (MT1 and MT2 receptors) agonist, e.g.,tasimelteon, is administered in a pharmaceutical formulation q.d. priorto the start of the target sleep time. It has been found that intreating Non-24, it is not necessary to administer the drug more thanabout 1 hour prior to the start of the target sleep time such that thedrug can be administered, e.g., at about 0.5 to about 1.5 hours prior tosleep time. Administration about 1 hour prior to sleep time isconvenient and useful. However, this invention also contemplatesadministration at earlier times in the day, e.g., about 2 hours, orabout 3 hours or even about 4 hours prior to target sleep time.

The ability to administer tasimelteon as little as about one hour priorto sleep time is advantageous because it allows for avoidance ofpre-sleep time soporific effects, because it allows for administrationof higher doses that might have greater soporific effects, and becauseit allows for pharmacologic intervention at a different phase of thesleep cycle than if it were administered earlier. Without wishing to bebound to any particular theory, it appears that the ability toadminister tasimelteon so close to sleep time is a function of itst_(max), which is approximately one-half hour. Melatonin, on the otherhand, which has a t_(max) of approximately 2 hours or more, isadministered several hours before sleep time, which can cause prematuresleepiness; to avoid this soporific effect, melatonin is sometimesadministered at sub-optimal doses.

Thus, in a related aspect, this invention comprises a method of treatingNon-24 patients, i.e., entraining such patients to a 24 hour circadianrhythm by internally administering an effective amount of a tasimelteonor another melatonin agonist that has a t_(max) of less than about 2hours, e.g., less than about 1.5 hours, or even less than about 1 hoursuch as about one-half hour like tasimelteon. Pharmaceuticalcompositions can be formulated so as to alter t_(max). Thus, e.g., useof an active pharmaceutical ingredient such as melatonin that isformulated such that its t_(max) is less than about two hours, e.g.,less than about 1.5 hours, or even less than about 1 hour, to treatNon-24 is an aspect of this invention.

Pharmaceutical compositions to be used comprise a therapeuticallyeffective amount of tasimelteon or an active metabolite of tasimelteon,or a pharmaceutically acceptable salt or other form (e.g., a solvate)thereof, together with one or more pharmaceutically acceptableexcipients. The phrase “pharmaceutical composition” refers to acomposition suitable for administration in medical use. It should beappreciated that the determinations of proper dosage forms, dosageamounts, and routes of administration for a particular patient arewithin the level of ordinary skill in the pharmaceutical and medicalarts.

Administration is typically oral but other routes of administration areuseful, e.g., parenteral, nasal, buccal, transdermal, sublingual,intramuscular, intravenous, rectal, vaginal, etc. Solid dosage forms fororal administration include capsules, tablets, pills, powders, andgranules. In such solid dosage forms, the compound is admixed with atleast one inert pharmaceutically acceptable excipient such as (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate, (e) solution retarders, as for example paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol, and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents. Solid dosage forms such as tablets,dragees, capsules, pills, and granules also can be prepared withcoatings and shells, such as enteric coatings and others well known inthe art. The solid dosage form also may contain opacifying agents, andcan also be of such composition that they release the active compound orcompounds in a certain part of the intestinal tract in a delayed manner.Examples of embedding compositions which can be used are polymericsubstances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients. Such solid dosage forms may generallycontain from 1% to 95% (w/w) of the active compound. In certainembodiments, the active compound ranges from 5% to 70% (w/w).

Solid compositions for oral administration can be formulated in a unitdosage form, each dosage containing from about 1 to about 100 mg ofactive ingredient. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired prophylactic or therapeuticeffect over the course of a treatment period, in association with therequired pharmaceutical carrier. Tasimelteon can be formulated, e.g., ina unit dosage form that is a capsule having 20 mg of active in additionto excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the compound or composition, the liquid dosage forms maycontain inert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances. Besides such inert diluents,the composition can also include adjuvants, such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

The present invention can be carried out in conjunction with othertreatment approaches, e.g., in combination with a second or multipleother active pharmaceutical agents, including but not limited to otheragents that affect insomnia, sleep-wake patterns, vigilance, depression,or psychotic episodes.

While this invention has been described in conjunction with the specificembodiments outlined above, it is evident that many alternatives,modifications and variations will be apparent to those skilled in theart or are otherwise intended to be embraced. Accordingly, theembodiments of the invention as set forth above are intended to beillustrative, not limiting. Various changes may be made withoutdeparting from the spirit and scope of the invention as defined in thefollowing claims. All patents, patent application, scientific articlesand other published documents cited herein are hereby incorporated intheir entirety for the substance of their disclosures.

1-66. (canceled)
 67. A method of entraining a patient's cortisolcircadian rhythm to a 24-hour circadian rhythm and maintaining said24-hour circadian rhythm, the method comprising: treating the patient byorally administering to the patient an effective amount of tasimelteononce daily before a target bedtime.
 68. The method of claim 67, whereinthe patient is light perception impaired (LPI).
 69. The method of claim67, wherein the patient is totally blind.
 70. The method of claim 67,wherein the patient suffers from Non-24-Hour Sleep-Wake Disorder. 71.The method of claim 67, wherein the 24-hour circadian rhythm comprises a24-hour sleep-wake cycle in which the patient awakens at or near atarget wake time following a daily sleep period of approximately 7 to 9hours.
 72. The method of claim 67, wherein the tasimelteon is orallyadministered 0.5 hours to 1.5 hours before the target bedtime.
 73. Themethod of claim 67, wherein treatment is initiated on a day in which thepatient's urinary cortisol acrophase is predicted to be within about 5.5hours before a target wake time and about 2.5 hours after the targetwake time.
 74. The method of claim 67, wherein treatment is initiated ona day in which the patient's urinary aMT6s acrophase is predicted to bewithin about 5.5 hours before a target wake time and about 2.5 hoursafter the target wake time.
 75. A method of synchronising a patient'scortisol circadian rhythm and melatonin circadian rhythm with a naturalday/night cycle, the method comprising: treating the patient by orallyadministering to the patient an effective amount of tasimelteon oncedaily before a target bedtime.
 76. The method of claim 75, wherein thepatient is light perception impaired (LPI).
 77. The method of claim 75,wherein the patient is totally blind.
 78. The method of claim 75,wherein the patient suffers from Non-24-Hour Sleep-Wake Disorder. 79.The method of claim 75, wherein the natural day/night cycle comprises a24-hour sleep-wake cycle in which the patient awakens at or near atarget wake time following a daily sleep period of approximately 7 to 9hours.
 80. The method of claim 75, wherein the tasimelteon is orallyadministered 0.5 hours to 1.5 hours before the target bedtime.
 81. Amethod of preventing or treating a disorder associated with adesynchronous cortisol circadian rhythm in a patient having adesynchronous cortisol circadian rhythm, said method comprisinginternally administering to the patient an effective amount oftasimelteon or an active metabolite thereof.
 82. The method of claim 81,wherein the patient is light perception impaired (LPI).
 83. The methodof claim 81, wherein the patient is totally blind.
 84. The method ofclaim 81, wherein the patient suffers from Non-24-Hour Sleep-WakeDisorder.
 85. The method of claim 81, wherein treatment is initiated ona day in which the patient's urinary cortisol acrophase is predicted tobe within about 5.5 hours before a target wake time and about 2.5 hoursafter the target wake time.
 86. The method of claim 81, wherein thetasimelteon is orally administered 0.5 hours to 1.5 hours before thetarget bedtime.
 87. A method of treating a patient suffering from Non-24comprising internally administering to the patient an effective amountof tasimelteon wherein the melatonin agonist agonizes MT1R and MT2R.